Er 2018-00071

REVIEW
Genetics of Human Primary Hypertension: Focus on

Hormonal Mechanisms
Worapaka Manosroi1,2 and Gordon H. Williams1
1
Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical
School, Boston, Massachusetts 02115; and 2Division of Endocrinology and Metabolism, Faculty of Medicine,
Downloaded from https://academic.oup.com/edrv/article/40/3/825/5257798 by guest on 28 June 2021

Chiang Mai University, Chiang Mai 50200, Thailand
ORCiD numbers: 0000-0002-4804-1093 (G. H. Williams).
ABSTRACT Increasingly, primary hypertension is being considered a syndrome and not a disease, with the individual causes (diseases) having a
common sign—an elevated blood pressure. To determine these causes, genetic tools are increasingly employed. This review identified 62
proposed genes. However, only 21 of them met our inclusion criteria: (i) primary hypertension, (ii) two or more supporting cohorts from
different publications or within a single publication or one supporting cohort with a confirmatory genetically modified animal study, and (iii)
600 or more subjects in the primary cohort; when including our exclusion criteria: (i) meta-analyses or reviews, (ii) secondary and monogenic
hypertension, (iii) only hypertensive complications, (iv) genes related to blood pressure but not hypertension per se, (v) nonsupporting studies
more common than supporting ones, and (vi) studies that did not perform a Bonferroni or similar multiassessment correction. These 21 genes
were organized in a four-tiered structure: distant phenotype (hypertension); intermediate phenotype [salt-sensitive (18) or salt-resistant (0)];
subintermediate phenotypes under salt-sensitive hypertension [normal renin (4), low renin (8), and unclassified renin (6)]; and proximate
phenotypes (specific genetically driven hypertensive subgroup). Many proximate hypertensive phenotypes had a substantial endocrine
component. In conclusion, primary hypertension is a syndrome; many proposed genes are likely to be false positives; and deep phenotyping will
be required to determine the utility of genetics in the treatment of hypertension. However, to date, the positive genes are associated with nearly
50% of primary hypertensives, suggesting that in the near term precise, mechanistically driven treatment and prevention strategies for the
specific primary hypertension subgroups are feasible. (Endocrine Reviews 40: 825 – 856, 2019)
H ypertension is the leading contributing factor

to all-cause global mortality. It is the main risk
factor for stroke (ischemic and hemorrhagic) and cor-
sign—an elevated blood pressure. By the mid-th century
it was known that there were secondary causes of
hypertension. However, the hypothesis that nearly
onary artery disease. Furthermore, people with hyper- the entire “essential” population with hypertension is
tension are predisposed to renal failure, heart failure, composed of “secondary” subsets is a phenomenon of
peripheral vascular disease, and other medical conditions the st century. Thus, currently there are at least six
(). It is estimated that, worldwide, nearly . billion factors to consider when addressing the hypertension
adults (% of females and % of males age . years treatment dilemma described above.
old) have hypertension (). Successful treatment rates
vary from modest to poor. An acknowledged substantial • First, for % to % of people with hypertension,
contributor to this low success rate is the lack of definitive there is no specific cause. These individuals are
data as to the mechanism(s) for the hypertension in the grouped together in a single category—essential
individual patient and, therefore, the lack of therapy to (primary) hypertension. ISSN Print: 0163-769X
treat the specific underlying cause (“disease”) rather than • Second, nearly all the secondary forms of hy- ISSN Online: 1945-7189
the more distant sign—the blood pressure. pertension are due to dysfunction in one or more Printed: in USA
of the endocrine systems (). Copyright © 2019
Endocrine Society
Hypertension as a syndrome • Third, it has long been known that there is a
Received: 1 March 2018
An increasing body of knowledge that had its origin de- strong heritable component to hypertension with Accepted: 7 September 2018
cades ago suggests that hypertension is not a disease but a heritability estimates ranging from % to % in First Published Online:
syndrome whose individual diseases have a common the general populations (–). 24 December 2018
doi: 10.1210/er.2018-00071 https://academic.oup.com/edrv 825

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ESSENTIAL POINTS
· Primary hypertension is not a disease but a syndrome whose individual diseases have a common sign—an elevated blood
pressure
· Substantial preclinical and clinical data have documented that increased blood pressure and its accompanying substantial
cardiovascular risks are largely secondary to the interplay between genetics and environment
·· Sixty-two genes were identified as potential candidates for this review
Only 21 of the 62 candidate genes met the following criteria: two supporting cohorts from different publications or two
different cohorts within a single publication or a single positive cohort with a confirmatory genetically modified animal
study
·· In all but three genes, deeper phenotyping studies beyond hypertension had been performed
Of the 21 genes, 18 were associated with salt-sensitive hypertension: 4 with normal renin levels, 8 with lower renin levels,
and 6 with undefined renin levels
·

These 18 genotype/phenotype groups are associated with nearly 50% of the primary hypertension population, suggesting
that precise mechanistically driven treatment/prevention strategies for the individual primary hypertension phenotypes
are feasible in the near term
• Fourth, substantial preclinical and clinical data have Linkage analyses usually require multigenerational
documented that an increased blood pressure and family data, although sometimes the approach uses
its accompanying substantial cardiovascular risks are data from affected sibling pairs (siblings both having
largely secondary to the interplay between genetics the same trait, e.g., hypertension). The hypothesis
and environment (–). being tested is based on Mendel’s second law of in-
• Fifth, for the past dozen years genome-wide as- dependent assortment: genetic traits should not be
sociation studies (GWASs) and whole-exome linked in different individuals; that is, variants in in-
sequencing techniques have revealed many po- dividual genes should not cosegregate (). Thus,
tential blood pressure–related pathways, but when variants in a gene do cosegregate with a trait in a
consistent associations with hypertension are family, this result provides strong evidence for linkage
infrequent to rare (, ). These results are of the gene to the trait and likely in a causative
not unique to hypertension, as similar results relationship.
(pathway gene variants but no consistent disease A much more common statistical approach is as-
variants) have been reported for other complex sociation analysis using a case control method. In this
chronic diseases, for example, anemia and di- approach relatedness is not required, but a “matched”
abetes mellitus (, ). control group is. This approach is increasing used in
• Sixth, it is evident that what are termed “chronic large-scale genetic studies (e.g., GWAS, exome, or
complex diseases” are not actually diseases but whole-genome sequencing) and often requires highly
syndromes, with several underlying diseases or sophisticated analytical techniques. “Big data” is the
causes potentially with their separate phenotype/ latest example of this approach. The overriding chal-
genotype relationships. Recently this has been lenge of these new approaches is not the quality of the
documented even with “rare diseases.” Some new genetic component of the genotype/phenotype associ-
rare diseases may be composites of two, or po- ation but the reliability of the phenotypic data. The
tentially more, separate genetic disease entities major hurdle to overcome for big data is the quality of
(causes) present in a single subject (). the clinical data used. This may be particularly chal-
These concepts have led to an increased emphasis on lenging for conditions such as hypertension where the
understanding the human phenome with the devel- so-called “disease” is actually a syndrome but coded in
opment during the past decade of tools to do so, for the medical records as a disease. Other challenges in-
example, the human Phenotype Ontology, Pheno- clude population stratification (namely, the separation
Miner, and Phenolyzer (–). of a study population into subgroups) and identification
of an appropriate control group. The latter challenge has
Linkage and association techniques been a major issue in studies of the genetics of hy-
Genetics studies fundamentally build on the premise pertension, because the control group needs to consist
that Mendel first demonstrated in the latter half of the of individuals who will always be normotensive—a
th century, namely, that a specific genetic locus difficult goal to achieve. Statistical evidence for an as-
(genotype) is associated with a trait (phenotype) and sociation between polymorphic variants of a gene and a
therefore causative of the trait. For many monogenic phenotype can occur because the variant itself is
conditions, linkage analyses have been used. functional and directly affects the expression of the
826 Manosroi and Williams Genetics of Human Primary Hypertension Endocrine Reviews, June 2019, 40(3):825–856
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phenotype; or it is correlated with, or in linkage dis- details as to how the studied population was selected.
equilibrium with, a closely associated causative allele; or Many published reports reviewed did not meet the
it is attributable to chance, artifact, or selection bias. appropriate standards. Those that did were carefully
Determining which of these conditions were met in controlled and/or assessed the clinical state of their
each study is often difficult. In this review, we have subjects, specifically in relationship to known envi-
attempted to address these challenges by reviewing the ronmental factors that can influence blood pressure.
Rationale for Choosing Specific genes involved with blood pressure control in the
Genes/Phenotype Associations physiologic range may not always lead to hyperten-
sion. Therefore, we have used the more stringent
This genetics of hypertension review is focused on phenotype—hypertension.
primary (essential) hypertension. The data are pre- The data used in this review were acquired from an
sented to emphasize that primary hypertension is a online search of the National Library of Medicine

syndrome, not a disease. Thus, we have expanded the using the PubMed search engine from January 
usual categorizing of hypertensive subgroups () into a through December . Our approach is summarized
traditional four-tiered genetic approach: (i) distant in Fig. . Specifically, the search terms “genes,” “ge-
phenotype (hypertension); (ii) intermediate phenotype netics,” “polymorphism with hypertension,” “blood
(salt-sensitive and salt-resistant hypertension); (iii) pressure,” “salt sensitivity,” and “salt-sensitive blood
subintermediate phenotypes under salt-sensitive hy- pressure” were applied. The criteria used for a gene to
pertension (normal renin and low renin); and (iv) be included in this review rested on three consider-
proximate phenotypes (specific genotype–driven hy- ations. (i) Many genes have been reported to be as-
pertensive subgroup) (Fig. ). Thus, this approach sociated with complex chronic phenotypes such as
first groups all hypertensive subjects into the most hypertension. With additional studies and analyses,
heterogeneous, distant phenotype (hypertension) and often these associations are not replicated, for example,
then successively subgroups them into increasingly in hypertension (). (ii) To reduce the number of
more homogeneous groups, with the proximate phe- potential false-positive associations, the criteria used
notype groups being the most homogeneous and herein are more restrictive than previous ones (). We
closest to the likely genetic mechanisms causing the reasoned that ideally every gene should have repli-
hypertension. Of importance, each genetic subtype of cation of supporting studies in different cohorts, an
primary hypertension has a substantial endocrine association with deep phenotyping supporting the
component, similar to what has been reported with proposed mechanism(s) causing of the hypertension,
secondary forms of hypertension. Finally, this review and animal- and cell-based studies that confirm the
includes studies of genotype/phenotype relationships linkage between altered gene function and the
where either all or many of the subjects have hy- mechanistic pathway causing the hypertension. (iii)
pertension. Studies where the phenotype assessed is However, in our review of the published data, we
only blood pressure per se and not hypertension are became concerned that we may exclude some likely
not included. Our reason to exclude these reports is genes because data to support all of the criteria noted
that both animal and human studies have noted that above were not available. Thus, we developed a
Figure 1. Categorization of the genotype/phenotypes of primary (essential) hypertension. The entities are grouped into increasingly
homogeneous physiological subgroups (distant, intermediate, subintermediate, and proximate phenotypes). The percentage, in
parentheses indicates the faction of the subentity for each of the preceding primary entities; for example, 60% of the population with
primary hypertension have salt-sensitive hypertension, and 55% of the group with salt sensitivity have low-renin hypertension.

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Figure 2. Flow diagram of process used to select genes for assessment of their relationship with primary (essential) hypertension. See
text for details.

restricted, but modified, set of criteria, and then statistics or that, when done, resulted in a
ranked each gene selected on the strength of the nonsignificant P value
available data. The following six inclusion criteria • Only nonhuman studies
were applied: For some genes, the strength of evidence supporting a
• English language publications relationship to hypertension was minimal or poor,
• Primary hypertension usually because the data available met only some but
• Hypertension as defined by the authors not all of our criteria. We have listed these genes but
• For each candidate gene, at least two supporting will not provide an assessment or references. For those
cohorts from different publications or two dif- genotype/phenotype groups where the strength of
ferent cohorts within a single publication or a evidence was fair or greater (each one meeting all
single supporting cohort with a confirmatory criteria), we have provided the following:
genetically modified animal study • Phenotype characteristics
• At least  individuals in the primary cohort • Genotype characteristics [in most cases, tagging
• In some cases, use of data before January , single-nucleotide polymorphisms (SNPs)]
usually to put the current data into perspective • Number of supporting and nonsupporting studies
The following seven exclusion criteria were applied: • Characteristics of genetically modified animal
• Results from meta-analyses or reviews models, if available
• Secondary hypertension and monogenic hy- • Pathophysiology linking the hypertension to the
pertension gene, if available
• Hypertensive complications unless related to • Therapeutic implications stemming from the
genes that met the primary inclusion criteria genotype/phenotype association, if available
• Genes related to blood pressure but not hyper- • Strength of evidence:
tension per se
• Genes where the number of supporting stud-
◦ the
Very strong—six or more supporting studies;
number of nonsupporting studies was
ies were less than twice the number of non- not .% of the number of supporting
supporting ones studies; salt sensitivity of blood pressure was
• Studies that did not perform a Bonferroni assessed in humans; and mechanistic human
or similar multi-assessment correction to their and/or animal studies were reported—that is,
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deep phenotyping or gene manipulation In each subsection, the genotype/phenotype groups

studies are listed alphabetically. Finally, we list, but do not
◦ Strong—two or more supporting studies; the
number of nonsupporting studies was not
review, the  genes that did not meet all of our
criteria. Each proximate genotype/phenotype group
.% of the number of supporting studies; usually will be identified by the name of the gene but,
salt sensitivity of blood pressure was assessed in a few cases, by the name of the phenotype.
in humans; and mechanisms were suggested
by human and/or animal studies Salt-sensitive, intermediate phenotype
◦ Moderate—two or more supporting studies;
the number of nonsupporting studies was
primary hypertension
Salt-sensitive, intermediate phenotype primary hy-
not .% of the number of supporting pertension has been the most commonly reported
studies; and salt sensitivity of blood pressure primary hypertension subset. Regardless of what
was assessed in humans and/or animals method has been used to assess salt-sensitive hyper-
◦ Fair—one or more supporting studies; the tension, this intermediate phenotype comprises ~%

number of nonsupporting studies was not to % of the primary hypertensive population, al-
.% of the number of supporting studies; though its prevalence varies somewhat in different
and no salt sensitivity of blood pressure or populations. Various mechanisms have been pro-
mechanistic studies were reported in humans posed to underlie salt-sensitive hypertension, but
or animals; when only one supporting study most involve renal dysfunction and/or dysfunction of
was reported, a confirmatory animal study an endocrine system, most commonly, the renin–
was required angiotensin–aldosterone system (RAAS) (–).
There was an extensive review of the genetics of Because the RAAS is involved in a volume, negative
hypertension published in  where the in- feedback loop, it has been assumed that subjects
formation was obtained from online searches of the with salt-sensitive hypertension will have a suppressed
National Library of Medicine using the PubMed RAAS, usually identified by a low renin or plasma
search engine from  to November  (). This renin activity (PRA) level. However, a low PRA state is
is the reason that this review consists of information
published since then. Importantly, the inclusion
criteria used in the previous review were not as
stringent as those used in the current review. Where
pertinent, the current review will include updated
information on the  genes described in the previous
review to provide an assessment of the long-term
sustainability of genotype/phenotype associations
in hypertension.
Summary of Selected Genotypes/Phenotypes
As stated above, we first review the  proximate,

genotype/phenotype groups that met our criteria and
were documented to have salt-sensitive, primary hy-
pertension [normal-renin () and low-renin () prox-
imate phenotypes] (Fig. ). For each proximate
phenotype, a figure has been included illustrating the
potential mechanism. For two proximate phenotypes,
where the evidence was the strongest, a specific figure is
provided. For the other  proximate phenotypes, where
Figure 3. Expansion of the categorization of the genotypes/phenotypes of primary (essential)
the evidence was not as strong, a figure is provided hypertension. The primary (essential) hypertension population (distant phenotype) can be divided
illustrating three general mechanisms for each gene. into two intermediate phenotypes (salt-resistant and salt-sensitive hypertension) based on their
We then review two other groups: six genes as- blood pressure response to changes in salt intake (liberal 2 restricted). Salt-sensitive hypertension
sociated with salt-sensitive blood pressure for which can be divided into two subintermediate phenotypes based on their renin (PRA) response to
renin status was not reported, and three genes that met upright posture and dietary salt restriction. Under each intermediate or subintermediate
phenotype, the individual proximate phenotypes are listed by the code for the gene. The
our criteria but for which data were not available to
percentage, in parenthesis, indicates the fraction of the subentity for each of the next above
determine whether the gene was associated with salt- primary entity; for example, 60% of the population with primary hypertension have salt-sensitive
sensitive or salt-resistant hypertension. There were no hypertension, 55% of the group with salt sensitivity have low-renin hypertension, and 5% of the
gene/phenotype subgroups that met our criteria and group with salt sensitivity and low renin carry the risk allele for ADD-1. Asterisks indicate that a
were documented to have salt-resistant hypertension. genetically altered animal model is available. NM, nonmodulation.

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only associated with % to % of the primary enhancing the efficiency of their interactions. Cav-
population with hypertension. Therefore, an equally eolae may also be involved in receptor-independent
large salt-sensitive hypertension subgroup must have endocytosis. Importantly, caveolae are rapidly lost
normal/high PRA levels. Thus, in this review, we in cell lines. Their loss could contribute to the dis-
divide the salt-sensitive hypertension intermediate crepancies in the time and dose response relation-
phenotype group into two subintermediate pheno- ships often reported in studies using cell cultures vs
types according to their renin-status: (i) normal/high those using acutely dispersed cells. In humans, there
renin and (ii) low renin. are three members of the caveolin family—caveolin-
(CAV-), caveolin-, and caveolin-. In vivo or acutely
Normal/high-renin, salt-sensitive, subintermediate ex vivo, caveolin-s are located on skeletal and cardiac
phenotype primary hypertension muscle, whereas CAV-s are located on all other cell
This group comprises individuals who have normal types. Caveolin-s are located on all cells and are usually
physiologic renin responses to sodium intake and physically associated with the other two caveolins. In
upright posture. Their normal renin status in the cultured cell lines, these relationships have been re-

presence of salt-sensitive hypertension suggests that ported to vary. CAV- has been the most extensively
these hypertensives have dysfunction not only in salt studied member of this family. It has been shown to
handling, but also in the normal RAAS physiologic interact with steroid, peptide, and adrenergic receptors.
response to inappropriate sodium retention. Ap- It also is known to bind to nitric oxide synthase, thereby
proximately % of hypertensives with salt-sensitive inhibiting its enzymatic activity ().
blood pressure (SSBP) belong to this salt-sensitive,
subintermediate phenotype hypertension group. Thus, Phenotype characteristics: The hypertensive phe-
~% to % of primary hypertensives have normal/ notype is driven as a component of the metabolic
high-renin, salt-sensitive hypertension. To date, all but syndrome. In white and Hispanic hypertensive
% to % of these individuals can be subgrouped cohorts, there was an association between CAV-
into four proximate phenotype groups (Fig. ). polymorphic variants and higher fasting insulin
Caveolin-1 gene (CAV1). Support for an as- and homeostatic model assessment of insulin
sociation of polymorphic variants in CAV and hy- resistance levels, thereby linking hypertension
pertension has been moderate during the past dozen and insulin resistance. However, there was an
years. However, it has become increasingly evident association between hypertension per se in
that the association between variants in CAV and Hispanics but not in whites (). The hyper-
hypertension is most likely to occur in the context of tensive subjects carrying the CAV- risk allele
the metabolic syndrome. Caveolins are a family of had normal PRA levels. Hypertension alone also
proteins that, as oligomers, associate with cholesterol was found to be related to CAV- polymorphism
and sphingolipids to form caveolae (). Caveolae in a Japanese cohort (). PRA levels were not
are specialized lipid rafts, located on the surface of reported. In a hypertensive cohort, low high-
nearly all cells. They are - to -nm hourglass density lipoprotein and metabolic syndrome
invaginations that function as scaffolding proteins were associated with a CAV- risk allele. In-
compartmentalizing and concentrating signaling mol- terestingly, although the association was sup-
ecules and their receptors and channels, thereby ported in the entire population, it was largely
driven by the nonobese subjects (, ). In
in silico analyses, this risk allele was associated
with decreased CAV- expression. Although no
nonsupporting correlations between CAV-
polymorphisms and hypertension have been
reported, one study did report a supporting
association between CAV- gene variants and
hypertension associated with the metabolic
syndrome but not in its absence (). Thus, the
clinical phenotype associated with the CAV-
risk allele consists of hypertension in normal
renin subjects who also have insulin resistance
and the metabolic syndrome, but not obesity.
Genotype characteristics: Various SNPs of CAV
have been studied regarding association with
hypertension alone or in association with the
Figure 4. The hypertension subintermediate phenotype group with salt-sensitive blood pressure
and normal renin status. All hypertensive subjects had substantial blood pressure responses to metabolic syndrome. They include rs,
dietary salt intake but normal renin (PRA) responses to upright posture and dietary salt restriction. rs (in complete linkage disequilibrium in
Asterisks indicate that a genetically altered animal model is available. NM, nonmodulation. some populations with rs), rs, and
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rs (–). In one study an insertion/ hypertension identified (, ). Its characteristics have
deletion polymorphism was used (). been confirmed around the world (–). Non-
Number of supporting and nonsupporting studies: modulation is a salt-sensitive hypertension phenotype
There have been three supporting (–) and () comprising % to % of hypertensives. Finally, it
one nonsupporting () association studies be- is one of the more complicated phenotypes to identify.
tween CAV and hypertension. Phenotype characteristics: The term nonmodulation
Availability and characteristics of genetically mod- comes from the absence of a common physio-
ified animal models: There have been extensive logic trait documented in normal humans and
cardiovascular and metabolic studies in the animals. The level of salt intake changes the
CAV- knockout mouse. Disruption of the vascular and aldosterone responses to angio-
CAV-/insulin receptor complex is associated tensin II (ANGII) in a teleologically important
with impairment of the insulin signaling pathway: when salt intake is reduced, the aldosterone
way (, ). This disruption leads to insulin response to ANGII is increased and the vascular
resistance, diabetes, increased triglyceride levels, response is reduced, whereas salt loading pro-

and salt-sensitive hypertension (i.e., the meta- duces the opposite responses. This salt intake–
bolic syndrome). However, these mice are not mediated modulation of target tissues responses
fat, but are skinny, similar to the humans car- to ANGII is absent in nonmodulators. Thus,
rying the CAV- risk allele (–). The CAV- nonmodulators on a low-salt diet do not have the
knockout mice also have dysregulated aldoste- anticipated enhanced aldosterone response to
rone secretion with increased endothelial nitric ANGII (causing their normal renin status), and
oxide synthase (eNOS) activity, presumably on a liberal salt diet the renovascular response to
secondary to the absence of the inhibitory effect ANGII is not modified from the low-salt state,
of CAV-. Their hypertension likely is secondary causing inappropriate renal vasoconstriction,
to increased vasoconstrictor activity, assessed ex sodium retention, and salt-sensitive hyper-
vivo, and the dysfunction in aldosterone secre- tension. Thus, phenotypically, to distinguish
tion. Their hypertension is salt sensitive and nonmodulators from other individuals with salt-
normal renin. Both the hypertension and the sensitive hypertension requires an assessment
vascular dysfunction are normalized by salt re- of aldosterone responses to ANGII on a low-salt
striction or mineralocorticoid receptor (MR) diet or renal blood flow response to ANGII on a
blockade (, ). These mice also have histo- liberal salt diet. However, because antihyper-
logic and molecular markers for cardiovascular tensive medications need to be stopped, careful
and renal damage. It is postulated that the control of salt intake is required, and an infusion
damage is secondary to pathologically increased of ANGII must be given to identify non-
nitric oxide activity resulting in increased pro- modulators clinically, which usually requires a
duction of reactive oxygen species. clinical research unit. In such a facility and with
Potential mechanisms linking hypertension to the the appropriate environmental controls, non-
gene: Based on the preclinical data, the associ- modulators have the following phenotypic
ation between decreased CAV- expression and characteristics: blunted renovascular and aldo-
the metabolic syndrome and hypertension, in sterone responses to Na1 intake and to AngII
part, is mediated by (i) insulin resistance, (ii) (–); a high degree of heritability (nearly %
inappropriate aldosterone secretion, and (iii)
enhanced vasoconstrictor activity (Fig. ).
Therapeutic implications stemming from the ge-
notype/phenotype association: Given the clini-
cal and preclinical data, one would assume that
the blood pressure in CAV- risk allele carriers
(vs noncarriers) would be more responsive to
insulin sensitizers (e.g., metformin), MR anta-
goinists (MRAs), and/or vasodilators. However,
no clinical studies have been reported associating
CAV- allele status and blood pressure response
to treatment with these agents. Of importance,
the CAV- risk allele is present in nearly % of
whites, blacks, and Hispanics.
Strength of evidence: moderate Figure 5. Relationship of genotype/phenotype group to mechanism of hypertension. The
Nonmodulation (NM). This subtype is one of genes are divided into three broad mechanistic categories—those associated with dysregulated
the few that is identified by its proximate phenotype. It is aldosterone secretion, those primarily associated with renal or renovascular dysfunction, and those
also one of the earliest proximate phenotypes of primary associated with both renal and adrenal dysfunction. NM, nonmodulation.

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of nonmodulators have a family history of hy- classical for nonmodulators. Other common hap-
pertension); increased circulating angiotensi- lotypes were not associated with characteristics of
nogen (AGT) () levels; delayed Na1 excretion nonmodulators despite the presence of the rs
after salt loading; and insulin resistance (, , and rs risk alleles (-A and T, respectively),
). Importantly, in a clinical research cen- suggesting that the AGT haplotype H is more
ter setting the defects underlying this sub- predictive of nonmodulators than are the single
intermediate phenotype can be corrected by SNPs -A or T. Their findings may explain
blocking the activity of the renin–angiotensin some of the discrepancies in clinical results using
system (, –). Additional clinical charac- AGT SNPs to predict the response to therapy.
teristics associated with hypertensives that carry Additionally, prior published data regarding AGT
the AGT risk allele, but not necessarily associated T and other SNPs assessed the association be-
with nonmodulation, include subarachnoid hem- tween this gene and primary hypertension without
orrhage, renal cyst, coronary artery disease, and addressing the subjects’ renin status (–).
preeclampsia (–). Number of supporting and nonsupporting studies:

Genotype characteristics: The genetics of non- There were six supporting and one non-
modulation originally were identified by poly- supporting association studies between AGT and
morphic variants in the AGT gene [the promoter hypertension (–).
A-C (rs) and the coding T (C: Availability and characteristics of genetically mod-
rs) SNPs] (, ). Several additional studies ified animal models: Deficiency of AGT in male
have associated these same AGT SNPs [and/or mice results in substantial hypotension ().
A-C (rs)] with hypertension, but data Furthermore, two relevant preclinical studies
regarding PRA status and salt-sensitive hyper- have been reported where human AGT has been
tension have not always been provided (–). overexpressed. When the human AGT is over-
To better understand the relationship be- expressed in the renal proximal tubule, salt-
tween genetic variation of AGT and essen- sensitive hypertension is produced. Transgenic
tial hypertension, two additional studies have mice with the human -A haplotype have in-
been published. First, in white hypertensives, creased blood pressure compared with the hu-
Kosachunhanun et al. () reported the influ- man -G haplotype (, ).
ence of additional RAAS genes on aldosterone Potential mechanisms linking hypertension to the
response to ANGII on a restricted salt intake. gene: The proposed mechanism leading to salt-
Not only was AGT (T, rs) associated with sensitive hypertension in nonmodulators is the
nonmodulators, but also this association was failure of the renal vascular to appropriately
enriched when the subjects also carried risk al- vasodilate on a liberal salt diet. Thus, sodium is
leles for both rs and angiotensin-converting retained, volume is expanded, and salt-sensitive
enzyme (ACE: I/D) and even more so when hypertension develops. Although the response of
hypertensives carried risk alleles for three RAAS aldosterone to salt restriction is also defective,
genes: AGT plus ACE plus aldosterone synthase this does not appear to contribute to salt-
[cytochrome P family  subfamily B member sensitive hypertension, but it does provide an
 gene (CYPB): -T, rs] (). explanation for the normal PRA (Fig. ). [See
However, alone neither variants in the ACE
nor the CYPB was associated with non-
modulation. Second, Watkins et al. ()
suggested that the genetic linkage of non-
modulators is not with a single AGT SNP,
but with a haplotype. SNPs and AGT haplo-
types were tested for association with plasma
AGT levels, a phenotypic marker of non-
modulation (renal plasma flow), and primary
hypertension (). Associations were reported
for alleles -G, A, A, C, and
C in addition to previous associations
for -T, -T, -A, -A, and T. Most
individually associated SNPs, including -A
and T, were found on a common complete
AGT haplotype, H (frequency, .). Individuals
with haplotype H had significantly higher plasma
AGT and reduced renal plasma flow (P , . Figure 6. Pathophysiologic mechanism causing salt-sensitive
and P , ., respectively), characteristics hypertension in the AGT gene/NM subgroup.
REVIEW
Table  (, , –, –, , –) for

nonmodulating phenotypic characteristics.] Table 1. Characteristics Associated with the
Nonmodulating Phenotype
Therapeutic implications: The AGT risk alleles as-
sociated with nonmodulators were assumed to • Decreased aldosterone response to ANGII when salt References are given in
be good biomarkers for individuals who pref- restricted (37, 42–48) parentheses.
erentially would respond to ACE inhibitors. Risk • Decreased renal plasma flow response to ANGII when salt
vs nonrisk allele carriers of AGT-A had a loaded (37, 38, 44–48)
greater blood pressure response to atenolol in a
• Decreased renal plasma flow response to salt loading (44,
Swedish population, to a thiazide diuretic in
45)
black women, and to an ACE inhibitor in a
Chinese population. In an Indian population, • Decreased sodium excretion with acute and chronic salt
risk vs nonrisk allele carriers of AGT T had a loading (75, 76)
better blood pressure response to ACE inhibitors • Increased blood pressure response to chronic salt loading
(, , , ). However, the results from other (75)

observational or post hoc analyses of hyperten-
• Decreased PRA response to acute salt loading (77, 78)
sion clinical trials have been mixed (–), with
one study suggesting that the AGT risk allele • Correction of above conditions with ACE inhibitor
appeared to blunt the blood pressure response to administration (38, 52–55)
an ACE inhibitor (). The reasons for these
• Increased family history of coronary disease (41)
discrepancies could be related to: (i) the re-
liability of observational/post hoc analyses; (ii) the • Increased plasma and urine dopamine levels (79)
uniqueness of AGT in mediating the non- • Increased sodium–lithium countertransport levels (80)
modulation phenotype; and/or (iii) the reliability
of the genetic biomarker used as suggested by • Associated with specific polymorphisms in AGT gene
Watkins et al. (). Furthermore, these results (45–49, 66)
also raise a note of caution regarding the utility of • Increased PAI-1 levels (81)
data obtained from clinical trials where the
subjects have not been randomized by genotype • Insulin resistance and increased total, low-density
lipoprotein cholesterol, and triglyceride levels (41, 82)
at the trial’s initiation.
Strength of evidence: very strong • Low frequency in premenopausal women (83)
Renin gene (REN). Renin is an enzyme pri- • Increased plasma AGT (46)
marily located and secreted from the juxtaglomerular
apparatus of the kidney. Most of the circulating renin
comes from this source. However, it is also synthesized
and secreted in a paracrine and autocrine fashion rs (, –). In one study an insertion/
from a variety of tissues, including, heart, fat, vascu- deletion polymorphism was used ().
lature, and adrenal. Functionally its substrate is usually Number of supporting and nonsupporting studies:
AGT to form the product angiotensin I (mostly in- There have been four supporting (, –) and
active) that is rapidly converted into ANGII, with the two nonsupporting (, ) association studies
active product of this cascade having several biologic between REN and hypertension.
effects, for example, vasoconstriction and aldosterone Availability and characteristics of genetically
stimulation (, ). modified animal models: The ANGII-induced
Phenotype characteristics: Polymorphic variants in increase in blood pressure was attenuated in
REN have been reported to be associated with collecting duct-specific REN knockout mice
SSBP (). Furthermore, on a liberal salt diet the (). In a cell-based study, the REN risk allele
risk allele and a haplotype were associated with promoter was associated with increased re-
higher supine PRA and reduced blood pressure nin expression (). These data suggest that
response to infused ANGII (). Women who rs is a functional variant. However,
were postmenopausal with hypertension that there have been no confirmations of this
carried the REN risk allele had significantly report.
higher blood pressure than did noncarriers Potential mechanism linking hypertension to the
(–). PRA status and SSBP were not reported gene: Variance in REN expression could result in
in these latter studies. However, a minimal as- increased renin levels resulting in increased
sociation between REN and hypertension, as a generation of ANGII, thereby increasing aldo-
state, also has been reported (). sterone secretion and vasoconstriction (spe-
Genotype characteristics: Various REN SNPs have cifically renal vasoconstriction), resulting in
been used, including rs, rs, and salt-sensitive hypertension (). The presently

REVIEW
available data support this hypothesis, as carriers from restricted to liberal. Furthermore, serum
of the REN risk allele do have reduced blood aldosterone levels, renal expression of the MR
pressure response to infused ANGII, indicative and its genomic downstream targets serum/
of increased ANGII, at least at the level of glucocorticoid-regulated kinase , and epithe-
the vasculature (). However, increased ANGII lial sodium channel were increased in Strn1/2 vs
and/or aldosterone levels have not been reported wild-type mice on liberal sodium intake. In
to be associated with REN risk allele status (Fig. ). contrast, the pAkt/Akt ratio, a readout of the
Therapeutic implications stemming from the genotype/ MR’s rapid, nongenomic pathway, was reduced.
phenotype association: Given the clinical and Furthermore, striatin deficiency was associated
preclinical data, one would assume that the with enhanced vasoconstriction and decreased
blood pressure in carriers vs noncarriers of the vascular relaxation, suggesting a critical role for
REN risk allele would be more responsive to striatin, through modulation of endothelial nitric
ACE inhibitors, angiotensin receptor blockers, or oxide–cGMP, in the regulation of vascular
renin inhibitors. However, no studies have been function and blood pressure during changes in

reported associating REN allele status and blood sodium intake. Finally, aldosterone, but not es-
pressure response to treatment. tradiol, increased striatin protein levels in en-
Strength of evidence: moderate/fair dothelial cells ().
Striatin gene (STRN). Striatin is a recently Potential mechanisms linking hypertension to the
described protein initially reported to be involved in gene: Both the carriers of the STRN risk allele
vesicular trafficking in neurons. It binds to CAV- and and the Strn1/2 mice have SSBP. From the
Ca1 calmodulin, GaI, and phosphatase A and studies in the Strn1/2 mice at least two mech-
regulates eNOS and MAPK (). It also has been anisms may contribute to this SSBP. First, the
documented that striatin mediates the rapid non- increased aldosterone levels on a liberal salt
genomic effect of steroids, specifically the MR and intake would lead to increased sodium retention.
Second, the decreased vasodilation, specifically in
estrogen receptor (ER)a (–). Striatin colocalizes
the renovasculature, on a liberal salt diet would
with the MR and modulates its nongenomic activity in
increase sodium reabsorption. Both abnormali-
vascular endothelial cells, that is, it rapidly increases
ties could be secondary to a reduction in cyclic
phosphorylation of ERK/ and AKT.
GMP (cGMP) levels on a liberal salt diet because
Phenotype characteristics: Studies assessing the as- cGMP inhibits aldosterone secretion and pro-
sociation between polymorphisms in this gene motes vasodilation (Fig. ).
and hypertension have been limited. Garza et al. Therapeutic implications stemming from the
() reported that there was a significant as- genotype/phenotype association: Given the clin-
sociation of STRN polymorphisms and SSBP in a ical and preclinical data, one would assume that
white population with hypertension. PRA levels the blood pressure in carriers vs noncarriers of
were normal in carriers of the risk allele. A the STRN would be more responsive to MRAs
subsequent study documented SSBP in risk allele or cGMP modulators. However, no studies have
carriers in individuals of African descent, nor- been reported that associate STRN allele status
motensives, and elderly subjects (). Currently, and blood pressure response to treatment with
there are no nonsupporting results regarding these agents.
STRN polymorphism and hypertension. Strength of evidence: moderate
Genotype characteristics: A haplotype analysis using
STRN-tagging SNPs defined three haplotype Low-renin, salt-sensitive, subintermediate
blocks. The global block analysis was signifi- phenotype primary hypertension
cantly associated with SSBP (Pglobal 5 .). This The normal response of an individual to intravascular
association was entirely driven by one haplotype volume expansion is to suppress the RAAS. By this
and specifically one SNP within that haplotype physiologic maneuver renal sodium absorption is
(rs) (, ). reduced both in the proximal tubule (in part, by in-
Number of supporting and nonsupporting studies: creased renal blood flow secondary to the reduced
There have been two supporting (, ) and ANGII) and in the distal tubule/collecting duct (by the
no nonsupporting association studies between reduction in aldosterone secondary to the reduced
STRN and hypertension. ANGII). Thus, the low-renin subintermediate phe-
Availability and characteristics of genetically mod- notype group comprises individuals who have had
ified animal models: SSBP was evaluated in the anticipated physiologic renin response to SSBP.
heterozygote knockout mice (Strn1/2) (, Approximately % of subjects with salt-sensitive
). Compared with wild-type mice, Strn1/2 hypertension are part of this subintermediate phe-
mice exhibited a significant increase in blood notype. Thus, ~% to % of all primary essen-
pressure when sodium intake was increased tial hypertensives have low-renin, salt-sensitive
REVIEW
hypertension. To date, all but % to % of these and high low-density lipoprotein level (–).
individuals can be subgrouped into eight proximate Finally, there also are several reports where
phenotypes (Fig. ). no association with hypertension was found
(–). However, in all nonsupporting studies,
Adducin-1 gene (ADD-1). Polymorphic var- the characteristics of the populations analyzed
iants in ADD- was one of the earliest genetic factors were limited. With homozygosity in the minor
associated with salt-sensitive primary hypertension. allele being the driver of this association and its
Support for it has remained strong for nearly the past frequency being quite low, population charac-
two decades. Adducins are a family of cytoskeletal teristics, particularly of the control group, are of
proteins first described by Bianchi and colleagues substantial importance.
in the Milan hypertensive rat (). Subsequently, Genotype characteristics: The most extensive studied
Bianchi and colleagues () reported that poly- ADD- SNP has been rs (GT). In gen-
morphic variants in ADD- are associated with salt- eral, because of the low frequency of the minor
sensitive human hypertension. The adducin family allele, allele carrier status has been used. How-
consists of three proteins (a, b, and g) that form

ever, where a genotype analysis was used, the
heterodimers. The a and g proteins are found in most strongest effect on blood pressure, particularly
cells whereas the b protein is expressed mainly in the salt-sensitive hypertension, was associated with
brain and hematopoietic cells. Adducin binds to homozygosity of the minor allele. Individuals
calmodulin and serves as a substrate for protein ki- that fit this criterion comprise % to % of
nases A and C. Thus, in addition to the major role of the hypertensive population or ~% of the
adducins in maintaining the actin-based cytoskeleton, low-renin subgroup. Haplotype assessment has
they are also involved in signal transduction, cell-to- been inconsistently reported. The combined
cell contact information, and cell migration (). effect of ADD- polymorphism and poly-
Some studies suggest that a-adducin also interacts morphism in other genes that may be involved
with a-Na/K ATPase and thereby the Na/K pump in salt intake–mediated blood pressure path-
potentially in the kidney, heart, and brain (, ). ways has been reported. These included various
Each adducin is produced by a different gene, although combinations of the following: AGT, plasma
their structures are similar. For example, a-adducin is membrane calcium-transporting ATPase  gene
produced by ADD-. (ATPB), prostaglandin-endoperoxide syn-
Phenotype characteristics: ADD- polymorphism is thase  (PTGS), WNK, and neural precursor
widely known as a candidate gene influencing cell–expressed developmentally downregulated
blood pressure. In , Casari et al. () first gene -like (NEDDL) (). In each case the
reported an association between ADD- poly- combination appeared to be additive. However,
morphism and hypertension. Two years later this
same group reported that the association was
with salt-sensitive hypertension (). During
the past  years, this group and others have
expanded the description of this proximate
hypertensive phenotype’s characteristics. ADD-
polymorphism has been reported to be associ-
ated with low-renin hypertension in younger
subjects (, years old) in Japan () and in
whites in Europe and the United States (,
). These groups also have observed decreased
intracellular erythrocyte sodium content and
decreased sodium–lithium countertransport in
hypertensives homozygous for the risk allele.
Finally, a reduction in fractional excretion of
sodium (the percentage of the sodium filtered by
the kidney that is excreted in the urine) was
observed in risk vs nonrisk allele carriers
(–). Salt-sensitive hypertension without
low PRA levels was reported in a Chinese
population (). Other phenotypic character- Figure 7. The hypertension subintermediate phenotype
with salt-sensitive blood pressure and low-renin status. All
istics associated with carriers of the ADD- risk hypertensive subjects had substantial blood pressure responses
allele include impaired renal function, peripheral to dietary salt intake and low-renin (PRA) responses to upright
artery disease, coronary artery disease, increased posture and dietary salt restriction. Asterisks indicate that a
blood pressure response to cold pressure test, genetically altered animal model is available.

REVIEW
only a single publication supports each of these suggest that greater blood pressure reductions
results. with ramipril (likely by increasing renal blood
Number of supporting and nonsupporting studies: flow) and hydrochlorothiazide occur in carriers vs
There have been five supporting and two non- noncarriers of the ADD- risk allele (, ).
supporting association studies between ADD- Strength of evidence: strong.
and hypertension (, –, –). b2-adrenergic receptor gene (ADRb2).
Availability and characteristics of genetically modi- Support for polymorphic variants in ADRb associ-
fied animal models: The identification of this gene ated with hypertension has been variable for almost
as a potential candidate for human hypertension the past two decades. The b-adrenergic receptor is a
originated from animal studies in the Milan member of the G protein–coupled receptor family. It
hypertensive rat (). In this rat, there is in- is activated by epinephrine-type agonists that cause
creased expression of a-Na/K ATPase (the Na/K smooth muscle relaxation in the vasculature and
pump) in the kidney, suggesting that the increased bronchi and increased speed of contraction in skeletal
pump activity leads to salt-sensitive hypertension. and cardiac muscles. The receptor is a classical seven-

The linkage to humans occurred when poly- loop one spanning the plasma membrane ().
morphic variants in ADD- was associated with Because of b-adrenergic receptor’s effect on vascular
salt-sensitive hypertension in the Milan hyper- smooth muscle, bAR polymorphic variants and their
tensive rat vs normotensive littermates. A sub- association with hypertension have been extensively
sequent report identified that the GT SNP in studied. However, the findings have been mixed.
humans is associated with salt-sensitive hyper- Relevant to hypertension, bARs are also located on
tension (). The group then performed a cross- the adrenal glomerulosa cell, and bAR agonists can
over study between the Milan hypertensive and stimulate aldosterone secretion (, ).
normotensive rats where they introgressed the a-,
Phenotype characteristics: bAR has shown great
b-, and g-adducin genes from one strain into the
other. Their results strongly suggested that it was promise as one of the genes affecting blood
the a-adducin that confers the salt-sensitive hy- pressure via sympathetic nervous system–
pertension phenotype (). mediated effects on vascular tone and cardiac
Potential mechanism linking the hypertension to contractility. The gene has been widely inves-
the gene: Given the salt-sensitive hypertension, tigated as a potential genetic factor associated
the decreased renal fractional clearance of so- with hypertension with inconsistent results ().
dium, and the association between a-adducin However, Pojoga et al. () used a different
and the Na/K pump, the most likely mechanism approach. Based on the studies by Svetkey et al.
leading to SSBP is increased activity of the Na/K (), they documented that the ADRb locus
pump resulting in increased sodium reabsorp- was associated with salt-sensitive hypertension.
tion by the kidney, intravascular volume ex- This proximate phenotype not only had salt-
pansion, suppression of renin, and salt-sensitive sensitive hypertension, but also low PRA on a
hypertension (Fig. ). low-salt diet and increased aldosterone on a
Therapeutic implications stemming from the liberal salt diet (). That aldosterone was the
genotype/phenotype association: Clinical studies driver of this phenotype was supported by lower
serum potassium on the liberal salt diet in
carriers vs noncarriers of the risk diplotype ().
These findings were supported by a report of an
association between the ADRb locus and the
blood pressure response to the Dietary Ap-
proaches to Stop Hypertension diet. Risk allele
carriers vs noncarriers had a greater reduction in
blood pressure and a reduced PRA level in re-
sponse to the diet (). Association with primary
hypertension regardless of renin status has also
been reported (). Recently, Liu et al. ()
confirmed SSBP associated with the risk allele of
this gene in a Chinese cohort. Changes in blood
pressure associated with other phenotypes,
for example, coronary artery disease, obesity
(body mass index . kg/m), and nocturnal
nondipping of blood pressure, also have been
Figure 8. Pathophysiologic mechanism causing the salt- described (, –). Nonsupporting asso-
sensitive hypertension in the ADD-1 gene subgroup. ciation results have also been reported (, ).
REVIEW
Genotype characteristics: Although several ADRb Phenotype characteristics: Rossi et al. () stated
SNPs have been reported to be associated with that the variants of CYPB (-CT, rs)
hypertension, the most frequent ones have been alleles were frequently found in those with low-
GA (rs) and CG (rs). A renin hypertension. High plasma aldosterone
haplotype has been reported between the ho- concentration and a high aldosterone-to-renin
mozygote for the minor allele of rs ratio in hypertensives with CYPB variants
were reported in Indian and Chinese pop-
and the homozygote for the major allele of
ulations (, ). A report of CYPB var-
rs. The haplotype identified the salt-
iants associated with hypertension without
sensitive hypertension group better than either mentioning renin status was described in an
SNP alone (). One study reported that an Indian population (). Salt-sensitive hyper-
interaction of ADRb GA and the a allele of tension was demonstrated in a Japanese pop-
NOS was associated with the risk of hyper- ulation regardless of renin status (). In one
tension (). However, no confirming studies study, salt-sensitive hypertension was associ-

were reported. ated with polymorphic variants in CYPB but
Number of supporting and nonsupporting studies: only in subjects who carried the risk alleles
There have been five supporting and two non- associated with hypertension for AGT and ACE
supporting association studies between ADRb (). In addition to hypertension, polymorphic
and hypertension (, –, , ). variants in this gene have been associated with
However, all studies that assessed the relationship characteristics often linked to excess aldoste-
between genotype and SSBP were supporting. rone secretion: insulin resistance, metabolic
Availability and characteristics of genetically mod- syndrome, diabetes mellitus type II, ischemic
ified animal models: No studies assessing blood stroke, left ventricular hypertrophy, and pre-
pressure– or volume-mediated effects have been eclampsia (–).
reported in genetically modified animals. How- Genotype characteristics: The most frequently re-
ever, several studies have documented that the ported risk allele of CYPB associated with
bAR is located on the glomerulosa cell and that hypertension was -CT (rs). Other
activation and/or blockade will modulate aldo- variants reported in association with hyperten-
sterone secretion (, , ). sion included rs (, –). Finally, a
Potential mechanism linking the hypertension to recent report suggested that a rare variant
the gene: The salt-sensitive hypertension asso- rs also was associated with hyper-
ciated with variance at the ADRb locus are tension in a Chinese population ()
likely secondary to an inappropriate level of Number of supporting and nonsupporting studies:
aldosterone on a liberal salt diet (Fig. ). Seven supporting studies and two nonsupporting
Therapeutic implications stemming from the studies have been reported (, –, ,
genotype/phenotype association: The minor , ).
allele of Rs was reported to be asso- Availability and characteristics of genetically mod-
ciated with a better blood pressure response ified animal models: CYPB-deficient mice
to ramipril (). However, no confirmatory have hypotension with a dependency on high salt
studies have been reported. No studies assess- intake to maintain a normal blood pressure (,
ing the relationship of blood responses to ). Although deficiency is associated with poor
MRAs have been reported. pregnancy outcomes, it is not associated with
Strength of evidence: moderate for hypertension; preeclampsia (). To date, no studies have
strong for salt-sensitive hypertension. been reported using an overexpressing rodent
model.
Cytochrome P450 family 11 subfamily B Potential mechanism linking hypertension to the
member 2 gene (CYP11B2). CYPB encodes gene: One study reported that CYPB risk
aldosterone synthase, the last enzymatic step involved allele carriers had higher aldosterone levels in
in aldosterone biosynthesis. The synthesis of this response to salt intake that was not offset by
enzyme is regulated chronically by dietary sodium and lower renin levels. Therefore, inappropriate so-
potassium intakes. Decreased intake of sodium and dium retention occurred () (Fig. ).
increased intake of potassium result in increased al- Therapeutic implications stemming from the
dosterone synthase levels and activity. The mecha- genotype/phenotype association: One would
nisms responsible for the increased synthesis of the assume the CYPB risk allele carriers would
enzyme are unclear (). Increased aldosterone be particularly responsive to MRAs. No specific
production could lead to salt-sensitive hypertension. clinical trial data have been reported, but in an
Alterations in aldosterone secretion could be sec- observational study, risk allele carriers did have
ondary to variants of CYPB (, ). higher aldosterone levels, and both their blood

REVIEW
pressure and aldosterone levels were more re- be particularly responsive to MRAs. However,
sponsive to spironolactone (an MRA) (). there are no current trial data to support this
Strength of evidence: strong/very strong. hypothesis.
Strength of evidence: fair.
Cytochrome P450 family 17 subfamily A
member 1 gene (CYP17A1). CYPA codes for Endothelin-1 gene (EDN1). Endothelin-
CYPA an enzyme also known as a-hydroxylase protein encoded from EDN, produced and re-
and ,-lyase. Its a-hydroxylase activity is a major leased by vascular endothelial and smooth cells, is a
step in the production of steroids, specifically gluco- potent vasoconstrictor (). It also can stimulate
corticoids by adding a hydroxyl group at carbon  of aldosterone secretion and thus has many parallels
progesterone or pregnenolone. -OH progesterone to the renin–angiotensin system. Indeed, there are
then can be further converted to cortisol in a two- substantial interactions between the two systems
enzyme step process. By its lyase activity, both -OH (). The secretion and mechanism of action of
pregnenolone and -OH progesterone can be further endothelin- have been reported to be involved in
converted into androstenedione and dehydroepian- pulmonary vasculature, brain, ovary, and penile

drostenedione with further conversions leading to tes- erectile functions. Dysregulation has been implicated
tosterone and estradiol (, ). Substantial deficiency in a variety of disease states, including cancers, lower
in CYPA results in an infrequent form of congenital urinary tract dysfunction, obesity, renal dysfunction,
adrenal hyperplasia whose characteristics include de- aging, preeclampsia, and several cardiovascular syn-
ficiencies in cortisol and sex steroids and increases in dromes ().
mineralocorticoids, for example, -deoxycorticosterone Phenotype characteristics: Subjects with high
and aldosterone, and hypertension. endothelin- levels have an increased risk of low-
Phenotype characteristics: Polymorphic variants in renin hypertension (, ). Polymorphic
CYPA (e.g., rs) associated with hy- variants in EDN have been associated with low-
pertension were identified in one GWAS study renin hypertension and increased aldosterone/
() but not in another (). Several additional renin ratios in individuals of African descent,
studies have confirmed its association with hy- but not in whites (). The association of
pertension (, ). In a Han Chinese pop- variants in EDN with hypertension or blood
ulation, the risk allele also was associated with pressure changes has been reported in individ-
decreased PRA and serum potassium levels uals with other medical conditions, for example,
(), suggestive of increased mineralocorticoid rheumatoid arthritis and mild obesity (, ).
effect, and SSBP. However, there were no pub- EDN variants have been linked to preeclampsia
lished data in primary hypertensive patients in women living in India (). An association of
where measurements of aldosterone, deoxy- EDN and hypertension has been reported in a
corticosterone, or sex steroids were provided. Chinese population (, ). Finally, variants in
Genotype characteristics: The following SNPs have endothelin-converting enzyme- gene have been
been used in these reports: rs, rs, reported to be associated with hypertension in
and rs (, –). the Japanese population ().
Number of supporting and nonsupporting studies: Genotype characteristics: Polymorphic variants of
In this review, four supporting studies (, EDN have been extensively reported, with
–), two nonsupporting studies in adults rs and rs being the most frequent
(, ), and one nonsupporting study in ones reported in association with hypertension
children () have been reported. (–).
Availability and characteristics of genetically mod- Number of supporting and nonsupporting studies:
ified animal models: CYPA is not required to Five supporting studies (–, , ) and
make glucocorticoids in the mouse, but it is to two nonsupporting studies have been published
make androgens and estrogens. Thus, genetically (, )
modified mice for this gene have been used to Availability and characteristics of genetically mod-
assess sex hormone effects but not mineralo- ified animal models: Analogous to data in
corticoids or hypertension. humans, animal studies demonstrated that rat
Potential mechanism linking hypertension to the models of SSBP had enhanced activity of
gene: Based on the study cited above (), it is endothelin- (, ). There are no studies of
likely that carriers of the CYPA risk allele will END total knockout, as this deletion is em-
have mineralocorticoid-dependent, salt-sensitive bryonically lethal. However, the endothelial-
hypertension (Fig. ). specific knockout is associated with low blood
Therapeutic implications stemming from the pressure (). In our database search, there
genotype/phenotype association: One would were no published studies involving EDN
assume the CYPA risk allele carriers would overexpression.
REVIEW
Potential mechanism linking the hypertension to supporting association between ESR variants
the gene: Given the role of endothelin in the and hypertension regardless of sex has also
regulation of vascular tone and aldosterone se- been reported ().
cretion, the SSBP could be secondary to dys- Genotype characteristics: Multiple variants of ESR
function in either the vasculature (particularly linked to hypertension have been reported, in-
the renal blood flow) and/or the adrenal (al- cluding CT, rs, rs, rs
dosterone secretion) (Fig. ). and GA (, –).
Therapeutic implications stemming from the Number of supporting and nonsupporting studies:
genotype/phenotype association: Tan et al. There were three supporting studies with four
() suggested that individuals of African cohorts (, , ) and two nonsupporting
descent who carry the END risk allele may be studies (, ).
particularly response to MRAs based on their Availability and characteristics of genetically mod-
increased aldosterone/renin ratio. However, ified animal models: No direct evidence from
there are no clinical trial data to support this animal studies have been published. However, in

hypothesis. rodents, activation of ESR can prevent the
Strength of evidence: fair for hypertension in blacks. adverse cardiovascular effects of aldosterone
(, ).
Estrogen receptor b gene (ESR2). Hyper- Potential mechanism linking hypertension to the
tension in young women is uncommon compared gene: Manosroi et al. () documented that only
with men (young and old) and older women. Estrogen in premenopausal women were ESR variants
appears to protect most women against hypertension, related to salt-sensitive hypertension and an
with the incidence of hypertension increasing after elevated aldosterone/renin ratio on a liberal salt
menopause (estrogen deplete). Yet, genetic variations diet (Fig. ).
in the ER are associated with cardiovascular disease. Therapeutic implications stemming from the genotype/
Estrogen interacts with three receptors: ERa, ERb, and phenotype association: Manosroi et al. ()
G protein–coupled ER. ESR is the coding gene for proposed that the SSBP could be secondary to
ERb. ERb is predominantly expressed in the vascu- estrogen occupying an abnormal ERb resulting
lature where the binding of estrogen usually results “[LSD1] plays an important
in inappropriate aldosterone suppression. Thus,
in vasodilatation (, ). Because some premen- MR blockade may be a useful, precise way to
epigenetic role by regulating
opausal women develop hypertension, estrogen may gene transcription via
treat these young women with hypertension. alteration in histone
play a different role in these women. Strength of evidence: fair for hypertension in methylation.”
Phenotype characteristics: Only a few studies have women
been reported on an association of ESR var-
iants and hypertension, with controversial re- Lysine-specific demethylase 1 gene (LSD1 or
sults. Two studies reported no association with KDM1A). In , Shi et al. () isolated the first
blood pressure or the development of hyper- histone demethylase, LSD. It plays an important
tension with polymorphic variants in ESR epigenetic role by regulating gene transcription via
(, ). However, in a Chinese cohort, ESR alteration in histone methylation (). It acts spe-
variants contributed to hypertension, particu- cifically to demethylate two lysine sites on histone
larly in women with oral contraceptive use —K and K. When it demethylates K this opens the
(). A recent study in two cohorts provide histone structure and thereby promotes gene tran-
support for the findings in the Chinese study scription. In contrast, histone structure is tightened
(). A candidate gene association study with when LSD acts on the K site. Thus, LSD can act as a
ESR and SSBP was conducted in normotensive coactivator or corepressor. Of interest, interaction with
and hypertensive women (estrogen replete and steroid receptors fosters LSD activation at the K site
estrogen deplete) and men. Multivariate ana- and thereby enhances its role as a corepressor. LSD is
lyses between variants of ESR and SSBP coded by the KDMA gene.
documented that risk allele carriers had a sig- Phenotype characteristics: Polymorphic variants in
nificantly supporting association with SSBP KDMA (LSD) are associated with low renin,
driven by estrogen-replete women in both SSHT in two populations—African descent and
cohorts with neither estrogen-deplete women Hispanics—but not in whites (). However,
or men having any genotype/phenotype as- normotensive white risk allele carriers vs non-
sociation. Furthermore, these estrogen-replete carriers of LSD do show a steeper rise in their
risk allele carriers had increased aldosterone/ age-associated increase in salt-mediated blood
renin ratios with lower PRA levels. Thus, in- pressure (). Also, decreased plasma aldoste-
appropriately increased aldosterone levels on a rone concentration and decreased renovascular
liberal salt diet may mediate the SSBP. response to salt loading were depicted only in
No associations with ESR were identified. A blacks (, ).

REVIEW
Genotype characteristics: Two tagging SNPs have SSBP (–). Furthermore, one study docu-
been identified to be associated with hyper- mented that SGK risk allele carriers with SSBP
tension—rs and rs (, ). also had low PRA levels on a low-salt diet ().
They are both intronic. No haplotype analyses Finally, one study suggested that polymorphic
have been reported. The minor allele frequency variants of SGK were associated with the de-
is % in blacks and % in whites. Thus, po- velopment of hypertension during a .-year
tentially nearly a quarter of black hypertensives follow-up ().
may carry the LSD risk allele or most of this Genotype characteristics: The following SGK SNPs
racial group’s low-renin hypertension subset. were associated with hypertension: rs
Number of supporting and nonsupporting studies: and rs (). Associated with SSBP
There has been one supporting study with two were rs, rs, rs, rs,
different cohorts and no nonsupporting associa- and rs (, ) and to low renin levels
tion studies between LSD and hypertension (). rs and rs (). Of interest, in
Availability and characteristics of genetically mod- some studies the risk allele associated with SSBP

ified animal models: An LSD heterozygote was present in close to % of the study cohort
knockout mouse has been developed. The total ().
knockout is embryologically lethal. The LSD Number of supporting and nonsupporting studies:
heterozygote knockout vs the wild-type mouse There have been three supporting and no
develops salt-sensitive hypertension at about nonsupporting association studies between the
 year of age with suppression of PRA, expanded SGK and hypertension (–).
intravascular volume on a liberal salt diet, and Availability and characteristics of genetically mod-
enhanced sodium excretion in response to a salt ified animal models: Mice lacking the SGK gene
load. These characteristics are typical of what are unable to appropriately increase the ex-
occurs in low-renin humans with hypertension pression and activity of ENaC, leading to im-
(, ). Finally, ex vivo aortic vascular studies paired sodium reabsorption and mild hypotension
suggest that the LSD heterozygote knockout on a sodium-restricted diet and resulting in so-
mice have enhanced vascular contraction and an dium dependency to maintain blood pressure
altered nitric oxide–cGMP relaxation pathway in (). No data have been reported using an SGK-
response to a high-salt diet (). Importantly, all overexpressing rodent.
the animal studies were performed on male mice. Potential mechanism linking hypertension to the
Whether there is a similar response in female gene: Given SGK’s key role in modulating
mice is unknown. ENaC activity and sodium resorption, it is likely
Potential mechanism linking hypertension to the that overexpression of SGK would result in
gene:From the animal studies the defect in the increased sodium retention and salt-sensitive,
vasculature could be the link to the salt-sensitive low-renin hypertension. However, data to sup-
hypertension if the results observed in the aorta port this hypothesis are limited (Fig. ).
also occur in the renal vasculature. Normally when Therapeutic implications stemming from the genotype/
salt intake is increased, the renal vasculature dilates phenotype association: Blockade of SGK could
to increase flow and enhance sodium excretion. If provide precise therapy for hypertensives who
this renal vascular response is impaired, salt- are SGK risk allele carriers. Such individuals
sensitive hypertension could occur (Fig. ). may also be more sensitive to MRAs. However,
Therapeutic implications stemming from the no clinical trial data to support this hypothesis
genotype/phenotype association: Potentially, have been reported.
agents that can increased salt excretion would Strength of evidence: moderate.
be more effective in the LSD risk allele car-
riers (e.g., diuretics, ACE inhibitors, or MRAs). Undefined renin, salt-sensitive, subintermediate
Strength of evidence: moderate. phenotype primary hypertension
This group contains variants of genes associated with
Serum- and glucocorticoid-inducible kinase salt-sensitive hypertension where data are lacking
1 gene (SGK1). Serum- and glucocorticoid-inducible concerning the renin status of the subjects. Thus, in
kinase  (SGK) is an important regulator of epi- several respects the phenotypes associated with these
thelial Na1 channel (ENaC) activity. Thus, it is a prox- genes are less well characterized compared with those
imate effector of aldosterone’s modulation of sodium in subintermediate phenotypes . and . (Fig. ).
reabsorption. SGK’s expression is modified by min- Angiotensin-converting enzyme gene (ACE).
eralocorticoids, intravascular volume, glucocorticoids, ACE encodes an enzyme that converts angiotensin I to
and insulin (–). ANGII. It is one of the most studied genes related to
Phenotype characteristics: Individuals with poly- hypertension because ANGII is a potent vasocon-
morphic variants in SGK are associated with strictor, particularly on the renal vasculature, and
REVIEW
aldosterone secretagogue. Thus, the activity of ACE Bradykinin receptor B2 gene (BDKRB2).
and the regulation of its expression have been sub- BDKRB encodes bradykinin receptor B pro-
stantially investigated in cardiovascular diseases (). tein, a G protein–coupled receptor involving in the
Additionally, variants in the ACE gene have been kallikrein–kinin system (KKS). This receptor binds to
associated with cancer, sarcoidosis, and autoimmune bradykinin, which acts as a strong diuretic and potent
diseases (). Furthermore, antagonists of this en- vasodilator via promoting nitric oxide synthesis (,
zyme have been extensively used to treat cardiovas- ).
cular and renal diseases (, ). Of interest, ACE Phenotype characteristics: There have been few
not only activates a potent vasoconstrictor, it also studies assessing BDKRB polymorphisms in
inactivates a potent vasodilator—bradykinin (). hypertensive cohorts. One study reported that
Phenotype characteristics: Most of the available the association was with salt-sensitive hyper-
data support an association between ACE poly- tension in Asians of both sexes (). A second
morphism and hypertension or SSBP (, , study reported an increase in the prevalence of
). However, in some cases the supporting data the BDKRB risk allele in hypertensive blacks,

have not been with ACE alone but in combination but it did not assess SSBP (). Another re-
with polymorphisms in other genes in the RAAS or ported an association between the risk allele
related pathways (, ). For example, an as- and Indian hypertensives that was largely
sociation with the metabolic syndrome and/or driven by males (). No additional pheno-
insulin resistance has been documented in some typic characteristics were reported in these
studies, for example, with polymorphic variants of studies.
CAV (). Finally, some studies have supported a Genotype characteristics: The following variants have
relationship between ACE polymorphism and been used in these studies: rs, rs, and
pregnancy-induced hypertension/mild preeclamp- an insertion/deletion in exon  (–). Of
sia or type  diabetes mellitus (–). note, the frequency of the risk allele in blacks was
Genotype characteristics: Based on its involvement much higher than in whites.
in RAAS, this gene has been one of the most Number of supporting and nonsupporting studies:
substantially investigated for association with There were three supporting (–) and one
hypertension (). Most studies have used the nonsupporting () studies.
insertion/deletion polymorphism in intron . Availability and characteristics of genetically modified
Number of supporting and nonsupporting studies: animal models: In a BDKRB knockout mouse,
Association of variants in this gene and hyper- profound ANGII-induced hypertension occurred
tension was documented in four studies (, compared with wild-type littermates ().
–). One study did not support this as- Potential mechanism linking hypertension to the gene:
sociation (). The presumed mechanism responsible for the
Availability and characteristics of genetically mod- hypertension is a loss of function of the diuretic/
ified animal models: He et al. () reported that vasodilator properties associated with activation of
compared with the wild-type rat, the ACE-
silenced rat had a significantly reduced systolic
blood pressure.
Potential mechanism linking the hypertension to
the gene: ACE is a pivotal factor regulating
vasoconstrictor and hormonal-mediated, volume-
regulating factors. Kaplan et al. () have provided
evidence documenting that the SSBP associated
with ACE variants is secondary to incomplete
suppression of the RAAS on a liberal salt intake.
However, because of inconsistencies in the human
studies, it is unclear how critical ACE variants
are in mediating most of the pathophysiologic
characteristics associated with cardiovascular and
renal diseases.
Therapeutic implications stemming from the genotype/
phenotype association: ACE polymorphism has Figure 9. Groups with hypertension, salt-sensitive blood
pressure intermediate phenotypes (without renin status). All
been associated with greater blood pressure re- subjects with hypertension had substantial blood pressure
sponse to treatment with the ACE inhibitors responses to dietary salt intake, but renin status was not
enalapril and lisinopil (). provided. Asterisks indicate that a genetically altered animal
Strength of evidence: fair. model is available.

REVIEW
this receptor. However, no specific studies have provided three additional phenotypic charac-
been performed to test this hypothesis. teristics. (i) The hypertension phenotype was
Therapeutic implications stemming from the particular strong in females (). (ii) A longi-
genotype/phenotype association: None reported tudinal Korean cohort study suggested that an
to date. increased sodium intake increases the risk of
Strength of evidence: fair. developing hypertension in risk allele carriers vs
noncarriers (). (iii) The risk allele is associated
Electrogenic sodium bicarbonate cotransporter with hypertension in Chinese children ().
4 gene (SLC4A5). SLCA encodes Na1-HCO2  Genotype characteristics: rs was the most
cotransporter expressed in the distal nephron. This commonly documented SNP of ATPB asso-
transporter is involved in intracellular pH regulation ciated with hypertension, with rs,
and mediates Na1-HCO2  influx (, ). Recent rs, and rs also being used (,
evidence indicates that SLCA, which encodes NBCe, , , –).
is expressed and can act in the proximal tubule to Number of supporting and nonsupporting studies:
modify sodium and bicarbonate transport ()

Seven supporting (–, , –) and
Phenotype characteristics: Two studies and three no nonsupporting studies have been reported to
cohorts have documented an association be- date.
tween polymorphic variants in SLCA and Availability and characteristics of genetically mod-
hypertension (, ). One of the cohorts was ified animal models: Silencing the ATPB gene
black the other two were white. In the white using siRNA increased blood pressure and va-
cohorts, the association was with SSBP. In one soconstriction (). Also, an ATPB knockout
cohort, gene variants of NBCe increased so- mouse had substantially higher blood pressure
dium and bicarbonate transport in human than did wild-type littermates ().
proximal tubule cells (). No other phenotypic Potential mechanism linking hypertension to the
characteristics were provided in these studies. gene: One study based on an animal model
Genotype characteristics: Two SNPs have been re- proposed that ATPB may play a crucial role in
ported to date: rs and rs (, blood pressure control by altering calcium
). These two SNPs are in linkage disequilibrium. handling in vascular smooth muscle cells and
Number of supporting and nonsupporting studies: thereby vascular tone ().
There have been two supporting studies and Therapeutic implications stemming from the
three supporting cohorts reported (, ). No genotype/phenotype association: None reported.
nonsupporting studies have been reported to Strength of evidence: fair for SSBP; strong for
date. hypertension.
Availability and characteristics of genetically
modified animal models: SLCA acid-loaded Serine/threonine 39 gene (STK39). STK
knockout mice were linked to sodium retention encodes a serine/threonine kinase and is also known
and hypertension (). as a thiazide response gene. It has been shown to
Potential mechanism linking hypertension to the interact with WNK kinase to regulate the Na/Cl
gene: A loss-of-function mutation in SLCA cotransporter. Thus, this kinase acts as a mediator
could reduce the synthesis of the sodium bi- of renal sodium and chloride reabsorption as well as a
carbonate cotransporter, thereby increasing so- controller of salt transport in the regulation of osmotic
dium retention, SSBP, and hypertension (). cell volume (–).
Therapeutic implications stemming from the Phenotype characteristics: A GWAS study reported
genotype/phenotype association: None have been a strong association of STK’s common variants
reported. and hypertension in Amish subjects (). A
Strength of evidence: moderate. single study reported an association between
STK polymorphisms and SSBP (). All other
Plasma membrane calcium-transporting studies were linked with hypertension per se
ATPase 1 gene (ATP2B1). ATPB encodes plasma (–). None of these studies commented on
membrane calcium ATPase isoform , an enzyme the renin status of the subjects. Finally, in three
that removes bivalent calcium from intracellular stores populations there was no association between
against a very high concentration gradient. Therefore, hypertension and STK genotype, that is, Chi-
this enzyme plays an important role in calcium nese children, Korean adults, and Chinese adults
homeostasis (). (, , ).
Phenotype characteristics: Hypertension associated Genotype characteristics: rs is the most
with variants of ATPB has been documented frequently reported SNP of STK in relation-
in two large-scale GWASs (, ) and five ship to hypertension. However, other SNPs
cohort studies (, –). These studies also of STK also have been association with
REVIEW
hypertension, for example, rs, rs, or activity will modify the individual’s ability to
and rs (, , –). appropriately excrete sodium. Thus, WNK
Number of supporting and nonsupporting studies: deficiency likely will be associated with SSBP.
Five supporting studies (–) and three Therapeutic implications stemming from the
nonsupporting studies (, , ) have been genotype/phenotype association: Different re-
reported. sponses to a thiazide diuretic were documented
Availability and characteristics of genetically mod- to be related to WNK variants in hypertensive
ified animal models: None. subjects (). Two to four percent of the var-
Potential mechanism linking hypertension to the iation in blood pressure response to the diuretic
gene: Wang et al. () proposed that in in- could be attributable to the presence of a WNK
dividuals who carry the STK risk allele, a gain risk allele. Finally, the risk of developing hy-
in function occurs. If so, in the renal tubule pertension with bevacizumab is increase sixfold
STK expression would increase, consequently in carriers of the WNK risk allele.
reducing renal sodium excretion and thereby Strength of evidence: fair.

resulting in hypertension.
Therapeutic implications stemming from the genotype/ Salt-resistant, intermediate
phenotype association: Absence of a selective blood phenotype hypertension
pressure response to thiazide diuretics () brings This intermediate phenotype includes individuals with
into question the clinical relevance of Wang et al.’s no or minimal changes in blood pressure when salt
() hypothesis. However, intriguingly, hyper- intake is modified. Approximately % of hyperten-
tensive male carriers of the STK risk allele had sives worldwide belong to this group. There are
a substantial blood pressure response to the an- substantial racial and geographic differences in the
giotensin receptor blocker losartan (). number of subjects who have salt-resistant hyper-
Strength of evidence: fair. tension. There were no proximate phenotypes iden-
WNK lysine-deficient protein kinase 1 tified within this group that met our criteria for
gene (WNK1). WNK encodes cytoplasmic serine- inclusion in this review (Fig. ).
threonine kinase in the distal nephron. This kinase
activates SGK, resulting in the activation of ENaC and Undefined hypertension phenotype
sodium retention (). WNK mutation is known to This group comprises three genes whose phenotype
be associated with the rare monogenic hypertension was not specifically associated with either salt-sensitive
disease, Gordon hyperkalemia-hypertension syndrome or salt-resistant hypertension. It is likely that addi-
(pseudohypoaldosteronism type II) (). tional studies may further define the phenotypic
characteristics associated with these genes (Fig. ).
Phenotype characteristics: WNK variants have
been associated with hypertension in two studies Angiotensin receptor type I gene (AGTR1).
(, ). Neither study reported any other AGTR encodes angiotensin receptor type  (ATR), a
phenotypic features (e.g., SSBP or hormone cell surface receptor. ANGII and some of its analogs
levels), although one suggested that positive bind to this receptor. This interaction triggers a cas-
findings varied with the population studied. cade of events in targeted cells, resulting in, for
WNK variants also were associated with the risk example, vasoconstriction, increased aldosterone se-
of developing hypertension with bevacizumab cretion, suppression of renin, modulation of renal
treatment (). Bevacizumab, a monoclonal sodium resorption, increased vasopressin secretion,
antibody to vascular endothelial growth factor, is altered cardiac function, and changes in immune
used to treat gynecologic cancers. As many as a function (, ). Given ATR’s mechanism of
third of subjects treated with bevacizumab de-
velop substantial hypertension.
Genotype characteristics: Four SNPs have been
reported in these studies: rs, rs,
rs, and rs (, , , ).
Number of supporting and nonsupporting studies:
Two supporting (, ) and one non-
supporting () studies have been reported.
Availability and characteristics of genetically mod-
ified animal models: In WNK heterozygous
knockout mice, a significant decreased in blood
pressure was observed ().
Potential mechanism linking hypertension to the Figure 10. Groups with hypertension with undefined salt-
gene: It is assumed that variation in WNK levels sensitive blood pressure and renin status.

REVIEW
action, one would anticipate that it would be associ- mice, fed a high-fat diet, gained weight, had increased
ated with hypertension. However, support for this liver enzymes, and showed histologic evidence of
hypothesis has been mixed. marked inflammation that was similar to nonalcoholic
Phenotype characteristics: Polymorphic variants of steatohepatitis ().
AGTR were associated with hypertension in Phenotype characteristics: One large GWAS reported
subjects from India and in blacks, but not in an association between FGF and hypertension
Latinos. In one study, circulating levels of the (). Additionally, three case control studies have
ATR were greater in hypertensives than normal, shown this association. (, , –). One
but there were no differences in their levels by study suggested that FGF variants were associ-
genotype. One study in a white cohort, using ated with SSBP (). This finding was not
a haplotype approach, reported a modest re- confirmed in another study (). Another study
lationship between polymorphic variants in the reported that an increased body mass index in-
gene and hypertension. No study assessed SSBP creased the blood pressure difference between risk
or provided information on other potentially allele carriers and noncarriers ().

important factors (e.g., hormone levels, renal Genotype characteristics: The most common SNPs
function) (–). Two nonsupporting stud- used were rs and rs (, ,
ies have also been reported (, ). , –).
Genotype characteristics: Most studies used the Number of supporting and nonsupporting studies:
rs SNP, although rs also has been used Five supporting (, , , –) and one
(–). nonsupporting () studies are reported herein.
Number of supporting and nonsupporting stud- Genetically modified animal models: None reported.
ies: Three supporting (–) and two non- Potential mechanism linking hypertension to the
supporting (, ) studies have been gene: No specific mechanism has been suggested.
reported. Therapeutic implications stemming from the genotype/
Availability and characteristics of genetically mod- phenotype association: None reported.
ified animal models: A haplotype of AGTR in Strength of evidence: fair.
humans when inserted into a mouse’s genome G protein b3 subunit gene (GNB3). GNB
causes an increase in blood pressured and an encodes the G protein b subunit that is a component
increase in ATR mRNA levels in heart and of heterotrimeric G protein complexes. These com-
kidney (). plexes transduce signals from G protein–coupled re-
Potential mechanism linking hypertension to the ceptors to intracellular effectors, thereby facilitating
gene: The most common mechanistic hypothesis diverse physiological processes, including cardiovas-
is a gain of function of the AGTR gene, resulting cular and/or metabolic functions (, ). Animal
in increased ATR levels with consequent studies suggest that altered production of GNB could
increased vasoconstriction and hypertension. result in increased signal transduction, cell pro-
There is less evidence for increased aldosterone liferation, and enhanced vascular reactivity. Associa-
production, particularly chronically (). tion of this gene with hypertension is mixed.
Therapeutic implications stemming from the Phenotype characteristics: Besides hypertension,
genotype/phenotype association: Given the gain- other distinguishing characteristics included
of-function mechanistic hypothesis, one would increased aldosterone levels associated with in-
anticipate that subjects who carry the risk allele creased serum sodium, potassium, and creati-
for hypertension would have greater reductions nine levels; hyperreactivity to a cold pressor test;
in blood pressure when given an angiotensin obesity; and, specifically, with hypertension in
receptor blocker. Two studies, one in China and women who are postmenopausal (, –).
one in Sweden, did report this effect (, ). In the study that reported higher aldosterone
Strength of evidence: fair/poor. levels, it is unclear whether the increased levels
Fibroblast growth factor 5 gene (FGF5). were primary or secondary given the increased
FGF encodes a protein (FGF) that is a member of potassium and creatinine levels (). There
the fibroblast growth factor family. FGF possesses cell was a significant, twofold greater risk of car-
survival and mitogenic activities and is involved in diovascular events in a -year follow-up study in
multiple human biological processes, for example, cell hypertensive Chinese subjects homozygous for
growth, morphogenesis, tumor growth and invasion, the GNB risk allele vs nonrisk allele. Two
and tissue repair (). It is an oncogene, and therefore studies did not support an association between
its mechanism of action has been intensively in- GNB and hypertension.
vestigated in oncology. However, FGF may also be Genotype characteristics: The following SNPs have
involved in a variety of other cellular processes, in- been used: rs, rs, rs, rs,
cluding inflammation. For example, FGF knockout and rs (, –).
REVIEW
Number of supporting and nonsupporting studies: with essential (primary) hypertension (). Using similar
Four supporting (, –) and two non- criteria as used in the  review, an additional 
supporting (, ) studies have been published. genes were identified in the literature published between
Availability and characteristics of genetically mod-  and . Thus, using PubMed data, as of 
ified animal models: No genetically altered an- December ,  genes were associated with primary
imal model studies were reported. hypertension. However, only about a third of these
Potential mechanism linking hypertension to the genes () met the stricter criteria used for this review.
gene: No consistent mechanistic hypothesis has Of note, only  of the  genotype/phenotype associ-
been proposed. ations reported in the previous review are among the 
Therapeutic implications stemming from the genotype/ genes reported herein. Several factors likely contribute
phenotype association: A polymorphic variant in to both the increase in the number of genes identified
rs was linked to hypertensive responders to and the substantial dropout rate. First, the publication of
diuretics (). GWASs since the previous report identified several loci
Strength of evidence: fair. associated with hypertension. Second, none of the loci

identified in the GWAS reports covered areas where
Genes with insufficient evidence for association genes reported in the  review are located. Third,
with hypertension phenotype there was a substantial increase in the number of
The following  genes had some evidence for asso- publications designed to support or refute the findings
ciation with hypertension but did not meet all our from the GWASs. Many of these studies were negative.
inclusion/exclusion criteria: ADD [adducin  (b)], Fourth, to be included in the list of genes associated with
ADRAA (a adrenergic receptor), ADRB [b ad- hypertension, the current review required published
renergic receptor (b adrenoreceptor)], ANP (atrial results from at least two supporting cohorts (beyond a
natriuretic peptide), APOC (apoliprotein C III), finding in a GWAS), and nonsupporting studies could
CACNB (voltage-dependent L-type calcium channel not exceed supporting ones.
subunit b), CLCNKA (chloride voltage-gated channel The two GWAS reports were published in the same
Ka), CSK (C-terminal Src kinase), CYBA (cytochrome issue of Nature Genetics in . Their results sub-
B- a chain), DRD (dopamine receptor D), DRD stantially accelerated the number of genes potentially
“…62 genes were associated with
(dopamine receptor D), ECE (endothelin converting associated with hypertension. Loci potentially covering
primary hypertension.…Only
enzyme ), EDNRA (endothelin receptor type A),  genes were identified. Interestingly, only one gene about a third of these genes (21)
EDNRB (endothelin receptor type B), ELN (elastin), was identified in both GWASs. Of the  genes, five met met the stricter criteria used for
eNOS (NOS), ESR (ER), GYS (glycogen synthase the criteria used in the  review (), but only three of this review.”
), HSDB (b-hydroxysteroid dehydrogenase type these five also met the stricter criteria used in this review
), INSR (insulin receptor), JAG (Jagged ), KCNJ (CYPA, FGF, and ATPB). Thus,  years after
(potassium voltage-gated channel subfamily J member publication of these pivotal GWASs, only % of the
), KLKB (kallikrein B), LPL (lipoprotein lipase), potential genes are included in the present review. The
MOV (putative helicase), MTHFR (methylene tet- frequent failure of traditional candidate gene ap-
rahydrofolate reductase), NPR (matriuretic peptide proaches to support GWAS findings is not surprising
receptor A), NPR (natriuretic peptide receptor B), for several reasons. First, GWASs are sophisticated
NEDDL (neutral precursor cell expressed, develop- observational studies. Therefore, they are useful for
mentally downregulated -like), NOSA (nitric oxide nominating candidate genes, but they typically are
synthase A), NRC (nuclear receptor subfamily  unable to establish disease causality. In part, these two
group C member ), PLEKHA (pleckstrin homology GWASs affirm this conclusion because only one of the
domain containing A), PRKG (cGMP-dependent genes identified in one GWAS was found in the other
protein kinase ), PRRCA (proline-rich coiled-coil despite apparently similar populations, inclusion cri-
A), SAH (S-adenosyl-L-homocysteine hydrolase), teria, and statistical approaches. Furthermore, although
SCNNA (sodium channel epithelial  a subunit), new genetic loci potentially can be identified by
SCNNG (sodium channel epithelial  g subunit), GWASs, these loci often contain multiple candidate
SELE (selectin E), SHB (SHB adaptor protein ), genes, with some, but not all, contributing to the
UMOD (uromodulin), WNK (WNK lysine-deficient susceptibility to a disease. Second, GWAS may not be
protein kinase ). able to identify a causative gene that is in linkage
disequilibrium with some component of the loci
identified by GWASs but not the actual gene. Thus,
Discussion similar to microarrays, additional studies specifically
designed to test the validity of a GWAS proposed
During this century, the use of genetic techniques to candidate gene are required. Third,  years may be
uncover the mechanisms underlying hypertension has insufficient time to develop cohorts with the appro-
increased dramatically. In a  review, polymorphic priate phenotypes to test the validity of the genetic
variants in  genes were identified as being associated hypotheses generated from the GWASs.

REVIEW
Of interest, there were no reported association who are normotensive, which would be anticipated in a
studies using the more refined techniques of exome gene linked to SSBP in people with hypertension.
sequencing or whole-genome sequencing. These ap- No genotype/phenotype groups were associated
proaches are designed to provide a more precise with salt-resistant hypertension unless it was present in
structural view of an individual’s genome. However, it is one or more of the three genetic groups where salt
unclear whether, by themselves, these newer genetic sensitivity was not tested. There were no published data
analytical techniques will provide a clearer pathway to assessing SSBP in any of the  genes that did not make
personalized, precision medicine envisioned at the the final list. Given that in general only ~% of people
beginning of the genetics revolution  to  years ago. with hypertension have salt-sensitive blood pressure,
For most complex, chronic conditions such as diabetes, these findings are puzzling. They suggest that (i) our
asthma, heart failure, and particularly hypertension, estimate of salt-sensitive hypertension is too low, (ii)
more detailed phenotyping data will be required. assessing salt-sensitive hypertension is easier to do than
In addition to the benefits of more personalized, assessing salt-resistant hypertension, and/or (iii) salt-
precision medicine that genetics-based studies will resistant hypertension does not have a genetic com-

provide, they also are likely to reduce overall health ponent. Third,  of the  genes had animal- and/or
care costs. For the patient, these costs reductions will cell-based studies to support the mechanisms by which
fall into three general areas. First, rather than using a gene modification could lead to hypertension. All but
population treatment focus with a multistep “see what one of these involved genes associated with salt-sensitive
happens” approach, a limited number of targeted steps hypertension. Only occasionally did the  genes that
will be used. Second, because of increased compliance we did not extensively review have animal- or cell-based
and specific mechanism targeting, a reduction in organ studies. Fourth, volume-related biomarkers were used
damage secondary to more consistent control of blood in most of the  proximate phenotype groups. For
pressure will occur. Third, with a treatment strategy example, (i) renin status, assessed using controlled salt
based on targeting specific mechanisms, there will be a intake and posture protocols, was determined in studies
reduction in off-target side effects with their associated associated with  of the  genes. For all but  of these
costs. The pharmaceutical industry will also experience  genes, animal- and/or cell-based studies also were
cost savings. First, drug development costs will be performed. For one of these three, CYPA, the gene
reduced because a more responsive, genetically does not exist in rodents. Renin status was not assessed
identified, clinical trial cohort can be used, thereby in any of the  genes not on the final list. (ii) Aldo-
reducing the size and costs of randomized clinical sterone levels in serum and/or urine were measured in 
trials. Second, knowing the mechanisms to target will out of  of the renin-classified phenotype/genotype
reduce the preclinical development costs. Finally, both groups. All but one also had animal studies to support
factors will reduce the time required to bring an agent the mechanism of action resulting in hypertension.
to market, resulting in increased patent-protected There were several other isolated deep phenotyping
marketing time. characteristics in a few of the  genotype/phenotype
What were the characteristics shared by the  genes salt-sensitive hypertensive groups.
in the proximate phenotype group beyond fulfilling the Previously identified secondary forms of hyper-
initial selection criteria? First, in all but three genes, tension have been associated with a change in
deeper phenotyping studies, beyond hypertension, had structure either of an organ or the coding region of a
been performed. Indeed, several of these  proximate gene. Intriguingly, both the genetic and the deep
phenotypes did not associate with hypertension per se, phenotyping data suggest that these new genetically
but only with an intermediate phenotype. Importantly, identified secondary forms of hypertension are most
the phenotype/genotype associations in all nine genes likely associated with a change in a gene’s expression
from the  review that also are included in this rather than a change in its structure. How common are
review had their associations supported by deep phe- these genetically identified secondary forms of hy-
notyping data. For the other  genes previously re- pertension? Based on the prevalence of the risk alleles
ported, there were few additional association studies of the  genes associated with SSBP and considering
reported in the past dozen years and most of those the likelihood that some individuals will carry a risk
reported were nonsupporting. Second,  of the  allele from more than one gene, it is likely that nearly
genes support the premise that polymorphic variants half of the primary hypertension population will carry a
in a gene alone were insufficient to produce a level of risk allele from one or more of these  genes. Thus,
blood pressure high enough to be called hypertension. when validated with clinical trial data, the known causes
Gene variants and an appropriate environment (usually of hypertension may have increased from the % to %
liberal salt intake) were required. These  genes were (the currently defined secondary hypertensives) to
associated with a proximate phenotype that included nearly % of the hypertensive population.
SSBP and, therefore, salt-sensitive hypertension. In the The active phenotype used in all GWASs and many
other three, salt sensitivity was not assessed. However, candidate gene approaches reviewed herein has been
only a few of the studies documented SSBP in people hypertension with the control group consisting of
REVIEW
individuals with “normotension.” There are several as- Omics are powerful tools to accomplish this goal, but
sumptions on which the validity of these approaches they will only take us so far for complex patho-
rests. First, hypertension is a consistently defined entity. physiological entities such as hypertension if we fail
This assumption seems unlikely. During the past to seriously consider the intense phenotypic het-
 years, who has hypertension, and particularly at what erogeneity. Based on the articles reviewed herein, the
blood pressure level treatment should be instituted, has most likely way to accomplish this goal is to study
varied by as much as / mm Hg. Furthermore, the genotype/phenotype relationships in exquisitely
level of blood pressure used to define hypertension “deeply” phenotyped cohorts. Some of the articles
varies in different parts of the world. Also, when surveyed used such cohorts. These cohorts had the
treatment is stopped even for as long as a year, for some following two attributes: (i) individuals (with and
“hypertensives” blood pressure may not rise above the without hypertension) enrolled in a protocol where
normal range. Thus, comparing results from studies most of the environmental factors that could influ-
from different years or areas of the world are likely ence the activity of volume and vasoconstrictor
flawed. Second, hypertension and normotension can regulating systems had been controlled; and (ii) on

clearly be distinguished. This assumption seems unlikely. this controlled background, interventions (“stress
Nearly all, if not all, studies that have assessed blood tests”) were performed to nearly maximally stimulate
pressure levels in large populations have confirmed that and nearly maximally suppress the activity of these
blood pressure is a continuous, not dichotomous, var- regulating systems to uncover subtle mechanistic
iable. This fact likely explains the continuing change in dysfunctions that, with time, could lead to hypertension.
the criteria used to define hypertension. It is not a In the literature surveyed, however, there were at
specific blood pressure level that is unique, but rather least four critical findings absent from most of the
cardiovascular events that are associated with an im- publications reviewed that limited our ability to more
precise surrogate marker—blood pressure. Third, hy- precisely address the above hypothesis. First, in nearly
pertension is a disease. This assumption also seems all studies, a causative gene variation was not iden-
unlikely. Several lines of evidence, including the data in tified. The studies used either tagging SNPs from
many of the articles reviewed herein, support the hy- haplotype candidate gene analyses or from GWASs.
pothesis that hypertension is a syndrome composed of Second, only a few studies (LSD, ESR, EDN, AGT, “…hypertension is a syndrome
several disease states, each associated with dysregulation and STRN) assessed the effect of the risk allele on composed of several disease
of volume homeostatic and/or vasoconstrictor systems the intermediate and/or proximate phenotypes in a states, each associated with
that results in a common sign—an increased blood normotensive group. Because the genetic changes dysregulation of volume
pressure. The clinical expression of these dysregulations, observed are in the germline, one would anticipate homeostatic and/or
vasoconstrictor systems….”
that is, hypertension, takes time, usually years, to de- that people who are normotensive who carried the
velop. Thus, in contrast to the  review that orga- risk allele might also have the associated interme-
nized the data by systems (), the currently available data diate or proximate phenotype even though they
fit more logically in a blood pressure functional para- did not have the distant phenotype (hypertension).
digm. For example, in this review, some people with salt- Such information could provide clues to the mech-
sensitive hypertension had low renin levels, whereas anisms underlying the relationship between the risk
others did not. As would be anticipated, the mechanisms allele and hypertension. Third, there were no con-
underlying their hypertensive states differed. More than trolled trials where the subjects were randomized to
half of the group with low renin had evidence of in- treatment groups by their genotype status. Some of
creased aldosterone, whereas the group with normal the  proximate phenotype groups, particularly in
renin and salt sensitivity had more support for a vas- those where there were extensive data from deeply
cular, particularly renovascular, mechanism for the salt phenotyped human studies and genetically modified
sensitivity of their blood pressure. animals, are reasonable candidates for such trials.
What is required to test the hypothesis that hy- In this survey, the phenotypic findings were grouped
pertension is a syndrome composed of several disease by individual genes. However, it is likely that the
states as suggested by the articles surveyed for this subjects inherited risk alleles from several genes.
review? There are at least three major, current ob- However, there were only five studies where the effects
stacles: first, defining the phenotypic characteristics of of gene–gene interaction were reported (ACE/EDNRB,
each hypertensive disease; second, determining each ADD/ATPB, ADD/WNK/NEDDL, AGT/ACE, and
disease’s specific mechanisms; and third, identifying AGT/ACE/CYPB). Of interest, in none of the five
the specific individuals whose hypertension is caused cases did the phenotypic characteristics change, ex-
by each unique mechanism. These obstacles are cept to make more pronounced the phenotype as-
similar to those faced by other complex chronic sociated with polymorphic variants in the primary
conditions, for example, diabetes, asthma, congestive gene. For example, the AGT risk allele was associated
heart failure, and chronic anxiety states. Because of with SSBP, normal PRA, and reduced aldosterone
these obstacles, other “omics” in addition to genomics response to ANGII on a restricted salt intake. When
are being employed to identify potential mechanisms. the subject also possessed the risk allele for ACE, the

REVIEW
aldosterone response was further reduced; and when the detailed review list from the  that did not. Yet, to
the individual possessed the risk allele for AGT/ACE/ date, intermediate or more proximate phenotypes
CYPB, the blunted aldosterone response was even have been used infrequently to identify genes asso-
greater (). Of importance, in this cohort neither the ciated with hypertension. The reasons likely are related
ACE nor CYPB alone was associated with altered to the lack of appropriate “clean” data sets given, at
aldosterone response to ANGII. This characteristic least, seven factors:
occurred only when they were combined with AGT. • Determining who has hypertension, given its
None of the other phenotypic characteristics changed changing definition [compare recommendations
appreciably. These results suggest that the funda- in JNC and the  American College of
mental mechanism underlying the pathophysiology Cardiology/American Heart Association guide-
in these subjects did not change even though the lines (, )].
individuals possessed more risk alleles—the genetic • Criteria that are used to exclude secondary hy-
driver was defined primarily by the principal pertension are limited at best and nonexistent at
genotype/phenotype association. However, none of worst.

these studies has been replicated. • Usually hypertension per se is used as the phe-
There are several limitations to the conclusions notype, even though the term is describing a
drawn from this survey of the literature. First, only syndrome, not a disease.
the PubMed search engine was used. Other data • Most genetic factors related to primary hyper-
sources might have yield different results. Second, the tension likely involve a change in the regulation
key search words were limited to hypertension or of a gene’s transcription, not the structure of its
variants on that word. As noted above, some of the product, thereby requiring more detailed phe-
genotype/phenotype groups reported an association notypic data.
with an intermediate phenotype of hypertension and • Difficulty in determining who does not have
not hypertension per se. We in part compensated for primary hypertension makes determining who
this potential issue by also including “salt sensitivity” can serve as a control group also difficult.
and “salt-sensitive hypertension” in our search word • Environmental factors, particularly salt intake,
list. Third, we excluded publications of known mono- have a substantial impact on the primary hy-
genic and secondary causes of hypertension. Thus, our pertension phenotype expressed. Clinical data
list is not all encompassing of the genetics of hyper- likely have limited utility to overcome this
tension. Finally, definitive exclusion of known secondary problem.
causes of hypertension was infrequently reported. Thus, • The complex array of systems that could be
whether only subjects with primary hypertension were dysfunctional in people with hypertension results
included in these cohorts is uncertain. in a very heterogeneous cohort in the absence of
In conclusion, during the past dozen years, sub- deep phenotyping.
stantial progress has been made in identifying po-
tential genetic factors associated with the primary Thus, these challenges need to be addressed,
hypertension syndrome. This progress has been largely likely by developing better deep phenotyping ap-
driven by considerable improvement in the tools proaches. When accomplished, individualized, per-
needed to assess the human genome. Yet, the data sonalized therapy can be achieved by using a
obtained also support the conclusion that many of the three-step paradigm: by determining the specific mech-
proposed genes are likely false positives. Contrariwise, anisms of the individual diseases (causes) (usually
more consistent associations were reported because of with the assistance of genetically modified animal
refinements in phenotyping. However, improvements models); by identifying the specific person with the
in phenotyping appear to be more difficult to im- disease (using genotypes of the linked genes); and
plement than what has occurred with genotyping. finally, by defining the precise mechanistically driven
Specifically, the availability of even modestly deep treatment and prevention strategies for the indi-
phenotyping data was the most common factor dis- vidual primary hypertension diseases, that is, prox-
tinguishing the phenotype of the  genes that made imate phenotypes.
References
1. Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, 2. Agarwal A, Williams GH, Fisher ND. Genetics of secondary pediatric hypertension. Am J Hypertens.
Reynolds K, Chen J, He J. Global disparities of hy- human hypertension. Trends Endocrinol Metab. 2005;18(7):917–921.
pertension prevalence and control: a systematic 2005;16(3):127–133. 4. Biino G, Parati G, Concas MP, Adamo M, Angius A,
analysis of population-based studies from 90 3. Robinson RF, Batisky DL, Hayes JR, Nahata MC, Vaccargiu S, Pirastu M. Environmental and genetic
countries. Circulation. 2016;134(6):441–450. Mahan JD. Significance of heritability in primary and contribution to hypertension prevalence: data from
REVIEW
an epidemiological survey on Sardinian genetic mellitus: a systematic review and meta-analysis. 32. Cohen AW, Razani B, Wang XB, Combs TP, Williams
isolates. PLoS One. 2013;8(3):e59612. J Epidemiol. 2018;28(1):3–18. TM, Scherer PE, Lisanti MP. Caveolin-1-deficient
5. Hollenberg NK. Genes, hypertension, and in- 18. Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, mice show insulin resistance and defective in-
termediate phenotypes. Curr Opin Cardiol. 1996; Coban Akdemir ZH, Walkiewicz M, Bi W, Xiao R, sulin receptor protein expression in adipose tissue.
11(5):457–463. Ding Y, Xia F, Beaudet AL, Muzny DM, Gibbs RA, Am J Physiol Cell Physiol. 2003;285(1):C222–C235.
6. Hollenberg NK. A genome-wide search for sus- Boerwinkle E, Eng CM, Sutton VR, Shaw CA, Plon SE, 33. Kabayama K, Sato T, Saito K, Loberto N, Prinetti A,
ceptibility loci to human essential hypertension. Yang Y, Lupski JR. Resolution of disease phenotypes Sonnino S, Kinjo M, Igarashi Y, Inokuchi J. Disso-
Curr Hypertens Rep. 2001;3(1):7–8. resulting from multilocus genomic variation. N Engl ciation of the insulin receptor and caveolin-1
7. Dickson ME, Sigmund CD. Genetic basis of hy- J Med. 2017;376(1):21–31. complex by ganglioside GM3 in the state of in-
pertension: revisiting angiotensinogen. Hyperten- 19. Robinson PN, Köhler S, Bauer S, Seelow D, Horn D, sulin resistance. Proc Natl Acad Sci USA. 2007;
sion. 2006;48(1):14–20. Mundlos S. The Human Phenotype Ontology: a 104(34):13678–13683.
8. Hottenga JJ, Boomsma DI, Kupper N, Posthuma D, tool for annotating and analyzing human hereditary 34. Pojoga LH, Romero JR, Yao TM, Loutraris P,
Snieder H, Willemsen G, de Geus JC. Heritability and disease. Am J Hum Genet. 2008;83(5):610–615. Ricchiuti V, Coutinho P, Guo C, Lapointe N, Stone
stability of resting blood pressure. Twin Res Hum 20. Yang H, Robinson PN, Wang K. Phenolyzer: JR, Adler GK, Williams GH. Caveolin-1 ablation
Genet. 2005;8(5):499–508. phenotype-based prioritization of candidate genes reduces the adverse cardiovascular effects of N-
9. Frohlich ED. Treating hypertension—what are we for human diseases. Nat Methods. 2015;12(9): v-nitro-L-arginine methyl ester and angiotensin II.
to believe? N Engl J Med. 2003;348(7):639–641. 841–843. Endocrinology. 2010;151(3):1236–1246.
10. Williams GH, Fisher ND. Genetic approach to di- 21. Collier N, Groza T, Smedley D, Robinson PN, 35. Pojoga LH, Yao TM, Sinha S, Ross RL, Lin JC, Raffetto

agnostic and therapeutic decisions in human hy- Oellrich A, Rebholz-Schuhmann D. PhenoMiner: JD, Adler GK, Williams GH, Khalil RA. Effect of
pertension. Curr Opin Nephrol Hypertens. 1997;6(2): from text to a database of phenotypes associated dietary sodium on vasoconstriction and eNOS-
199–204. with OMIM diseases. Database (Oxford). 2015;2015: mediated vascular relaxation in caveolin-1-
11. Kupper N, Ge D, Treiber FA, Snieder H. Emergence bav104. deficient mice. Am J Physiol Heart Circ Physiol.
of novel genetic effects on blood pressure and 22. Mendel G. Experiments in Plant Hybridization 2008;294(3):H1258–H1265.
hemodynamics in adolescence: the Georgia Car- (1865). New York: Cosimo, Inc., 2008. 36. Pojoga LH, Adamová Z, Kumar A, Stennett AK,
diovascular Twin Study. Hypertension. 2006;47(5): 23. Fisher ND, Hurwitz S, Ferri C, Jeunemaitre X, Romero JR, Adler GK, Williams GH, Khalil RA.
948–954. Hollenberg NK, Williams GH. Altered adrenal Sensitivity of NOS-dependent vascular relaxation
12. Hedayati SS, Elsayed EF, Reilly RF. Non-pharmacological sensitivity to angiotensin II in low-renin essential pathway to mineralocorticoid receptor blockade in
aspects of blood pressure management: what hypertension. Hypertension. 1999;34(3):388–394. caveolin-1-deficient mice. Am J Physiol Heart Circ
are the data? Kidney Int. 2011;79(10):1061– 24. Chamarthi B, Williams JS, Williams GH. A mecha- Physiol. 2010;298(6):H1776–H1788.
1070. nism for salt-sensitive hypertension: abnormal di- 37. Shoback DM, Williams GH, Moore TJ, Dluhy RG,
13. Knight BS, Sunn N, Pennell CE, Adamson SL, Lye SJ. etary sodium-mediated vascular response to Podolsky S, Hollenberg NK. Defect in the sodium-
Developmental regulation of cardiovascular func- angiotensin-II. J Hypertens. 2010;28(5):1020–1026. modulated tissue responsiveness to angiotensin II
tion is dependent on both genotype and envi- 25. Pojoga L, Kolatkar NS, Williams JS, Perlstein TS, in essential hypertension. J Clin Invest. 1983;72(6):
ronment. Am J Physiol Heart Circ Physiol. 2009;
Jeunemaitre X, Brown NJ, Hopkins PN, Raby BA, 2115–2124.
297(6):H2234–H2241.
Williams GH. b-2 Adrenergic receptor diplotype 38. Redgrave J, Rabinowe S, Hollenberg NK, Williams
14. Zheng J, Rao DC, Shi G. An update on genome-wide
defines a subset of salt-sensitive hypertension. GH. Correction of abnormal renal blood flow re-
association studies of hypertension. Appl Inform
Hypertension. 2006;48(5):892–900. sponse to angiotensin II by converting enzyme
(Berl). 2015;2(1):10.
26. Lamaze C, Tardif N, Dewulf M, Vassilopoulos S, inhibition in essential hypertensives. J Clin Invest.
15. Warren HR, Evangelou E, Cabrera CP, Gao H, Ren M,
Blouin CM. The caveolae dress code: structure and 1985;75(4):1285–1290.
Mifsud B, Ntalla I, Surendran P, Liu C, Cook JP, Kraja
signaling. Curr Opin Cell Biol. 2017;47:117–125. 39. Uneda S, Fujishima S, Fujiki Y, Tochikubo O, Oda H,
AT, Drenos F, Loh M, Verweij N, Marten J, Karaman
27. Pojoga LH, Underwood PC, Goodarzi MO, Williams Asahina S, Kaneko Y. Renal haemodynamics and
I, Lepe MP, O’Reilly PF, Knight J, Snieder H, Kato N,
JS, Adler GK, Jeunemaitre X, Hopkins PN, Raby BA, the renin-angiotensin system in adolescents ge-
He J, Tai ES, Said MA, Porteous D, Alver M, Poulter
Lasky-Su J, Sun B, Cui J, Guo X, Taylor KD, Chen YD, netically predisposed to essential hypertension.
N, Farrall M, Gansevoort RT, Padmanabhan S, Mägi
Xiang A, Raffel LJ, Buchanan TA, Rotter JI, Williams J Hypertens Suppl. 1984;2(3):S437–S439.
R, Stanton A, Connell J, Bakker SJ, Metspalu A,
GH. Variants of the caveolin-1 gene: a translational 40. Ramirez AJ, Migliorini M, Gilbert BH, Marco EJ,
Shields DC, Thom S, Brown M, Sever P, Esko T,
Hayward C, van der Harst P, Saleheen D, investigation linking insulin resistance and hyper- Sanchez RA. Non-modulating essential hyperten-
Chowdhury R, Chambers JC, Chasman DI, tension. J Clin Endocrinol Metab. 2011;96(8): sion: renal hemodynamic effects of long-term an-
Chakravarti A, Newton-Cheh C, Lindgren CM, Levy E1288–E1292. giotensin converting enzyme inhibition. J Hypertens
D, Kooner JS, Keavney B, Tomaszewski M, Samani 28. Yamada Y, Ando F, Shimokata H. Association of Suppl. 1991;9(6):S396–S397.
NJ, Howson JM, Tobin MD, Munroe PB, Ehret GB, gene polymorphisms with blood pressure and the 41. Ferri C, Bellini C, Desideri G, Valenti M, De Mattia G,
Wain LV; International Consortium of Blood prevalence of hypertension in community-dwelling Santucci A, Hollenberg NK, Williams GH. Re-
Pressure (ICBP) 1000G Analyses; BIOS Consortium; Japanese individuals. Int J Mol Med. 2007;19(4): lationship between insulin resistance and non-
Lifelines Cohort Study; Understanding Society 675–683. modulating hypertension: linkage of metabolic
Scientific group; CHD Exome1 Consortium; Exo- 29. Baudrand R, Goodarzi MO, Vaidya A, Underwood abnormalities and cardiovascular risk. Diabetes.
meBP Consortium; T2D-GENES Consortium; PC, Williams JS, Jeunemaitre X, Hopkins PN, Brown 1999;48(8):1623–1630.
GoT2DGenes Consortium; Cohorts for Heart and N, Raby BA, Lasky-Su J, Adler GK, Cui J, Guo X, Taylor 42. van Hooft IM, Grobbee DE, Derkx FH, de Leeuw
Ageing Research in Genome Epidemiology KD, Chen YD, Xiang A, Raffel LJ, Buchanan TA, PW, Schalekamp MA, Hofman A. Renal hemody-
(CHARGE) BP Exome Consortium; International Rotter JI, Williams GH, Pojoga LH. A prevalent namics and the renin-angiotensin-aldosterone
Genomics of Blood Pressure (iGEN-BP) Consortium; caveolin-1 gene variant is associated with the system in normotensive subjects with hyperten-
UK Biobank CardioMetabolic Consortium BP metabolic syndrome in Caucasians and Hispanics. sive and normotensive parents. N Engl J Med. 1991;
working group. Genome-wide association analysis Metabolism. 2015;64(12):1674–1681. 324(19):1305–1311.
identifies novel blood pressure loci and offers bi- 30. Baudrand R, Gupta N, Garza AE, Vaidya A, Leopold 43. Beretta-Piccoli C, Pusterla C, Städler P, Weidmann P.
ological insights into cardiovascular risk. Nat Genet. JA, Hopkins PN, Jeunemaitre X, Ferri C, Romero JR, Blunted aldosterone responsiveness to angiotensin
2017;49(3):403–415. Williams J, Loscalzo J, Adler GK, Williams GH, Pojoga II in normotensive subjects with familial pre-
16. Chami N, Lettre G. Lessons and implications from LH. Caveolin 1 modulates aldosterone-mediated disposition to essential hypertension. J Hypertens.
genome-wide association studies (GWAS) findings pathways of glucose and lipid homeostasis. J Am 1988;6(1):57–61.
of blood cell phenotypes. Genes (Basel). 2014;5(1): Heart Assoc. 2016;5(10):e003845. 44. Hollenberg NK, Williams GH. Abnormal renal
51–64. 31. Grilo A, Fernandez ML, Beltrán M, Ramirez-Lorca R, function, sodium-volume homeostasis and renin
17. Kodama S, Fujihara K, Ishiguro H, Horikawa C, González MA, Royo JL, Gutierrez-Tous R, Morón FJ, system behavior in normal-renin essential hyper-
Ohara N, Yachi Y, Tanaka S, Shimano H, Kato K, Couto C, Serrano-Rios M, Saez ME, Ruiz A, Real LM. tension: the evolution of the nonmodulator con-
Hanyu O, Sone H. Quantitative relationship be- Genetic analysis of CAV1 gene in hypertension and cept. In: Laragh JH, Brenner BM, eds. Hypertension:
tween cumulative risk alleles based on genome- metabolic syndrome. Thromb Haemost. 2006;95(4): Pathophysiology, Diagnosis, and Management. 2nd
wide association studies and type 2 diabetes 696–701. ed. New York, NY: Raven; 1995:1837–1856.

REVIEW
45. Hopkins PN, Lifton RP, Hollenberg NK, Jeunemaitre and preeclampsia in Iranian pregnant women. angiotensinogen gene with essential hypertension:
X, Hallouin MC, Skuppin J, Williams CS, Dluhy RG, J Family Reprod Health. 2014;8(4):169–173. a meta-analysis. Genet Mol Biol. 2014;37(3):473–479.
Lalouel JM, Williams RR, Williams GH. Blunted renal 59. Kurland L, Liljedahl U, Karlsson J, Kahan T, 72. Yiannikouris F, Wang Y, Shoemaker R, Larian N,
vascular response to angiotensin II is associated Malmqvist K, Melhus H, Syvänen AC, Lind L. Thompson J, English VL, Charnigo R, Su W, Gong M,
with a common variant of the angiotensinogen Angiotensinogen gene polymorphisms: relationship Cassis LA. Deficiency of angiotensinogen in hepa-
gene and obesity. J Hypertens. 1996;14(2):199–207. to blood pressure response to antihypertensive tocytes markedly decreases blood pressure in lean
46. Watkins WS, Hunt SC, Williams GH, Tolpinrud W, treatment. Results from the Swedish Irbesartan Left and obese male mice. Hypertension. 2015;66(4):
Jeunemaitre X, Lalouel JM, Jorde LB. Genotype- Ventricular Hypertrophy Investigation vs Atenolol 836–842.
phenotype analysis of angiotensinogen poly- (SILVHIA) trial. Am J Hypertens. 2004;17(1):8–13. 73. Ying J, Stuart D, Hillas E, Gociman BR, Ramkumar N,
morphisms and essential hypertension: the 60. Yu H, Lin S, Zhong J, He M, Jin L, Zhang Y, Liu G. A Lalouel JM, Kohan DE. Overexpression of mouse
importance of haplotypes. J Hypertens. 2010;28(1): core promoter variant of angiotensinogen gene and angiotensinogen in renal proximal tubule causes
65–75. interindividual variation in response to angiotensin- salt-sensitive hypertension in mice. Am J Hypertens.
47. Patel TV, Williams GH, Fisher ND. Angiotensinogen converting enzyme inhibitors. J Renin Angiotensin 2012;25(6):684–689.
genotype predicts abnormal renal hemodynamics Aldosterone Syst. 2014;15(4):540–546. 74. Jain S, Tillinger A, Mopidevi B, Pandey VG, Chauhan
in young hypertensive patients. J Hypertens. 2008; 61. Li Q, Sun L, Du J, Ran P, Gao T, Yuan Y, Xiao C. Risk CK, Fiering SN, Warming S, Kumar A. Transgenic
26(7):1353–1359. given by AGT polymorphisms in inducing sus- mice with –6A haplotype of the human angio-
48. Hopkins PN, Hunt SC, Jeunemaitre X, Smith B, ceptibility to essential hypertension among isolated tensinogen gene have increased blood pressure
Solorio D, Fisher ND, Hollenberg NK, Williams GH. populations from a remote region of China: a case- compared with –6G haplotype. J Biol Chem. 2010;

Angiotensinogen genotype affects renal and ad- control study among the isolated populations. 285(52):41172–41186.
renal responses to angiotensin II in essential hy- J Renin Angiotensin Aldosterone Syst. 2015;16(4): 75. Hollenberg NK, Moore T, Shoback D, Redgrave J,
pertension. Circulation. 2002;105(16):1921–1927. 1202–1217. Rabinowe S, Williams GH. Abnormal renal sodium
49. Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, 62. Niu S, Zhang B, Zhang K, Zhu P, Li J, Sun Y, He N, handling in essential hypertension. Relation to
Williams CS, Charru A, Hunt SC, Hopkins PN, Zhang M, Gao Z, Li X, Simayi A, Ge J, Cong M, Zhou failure of renal and adrenal modulation of responses
Williams RR, Lalouel JM, Corvol P. Molecular basis of W, Qiu C. Synergistic effects of gene poly- to angiotensin II. Am J Med. 1986;81(3):412–418.
human hypertension: role of angiotensinogen. Cell. morphisms of the renin–angiotensin–aldosterone 76. Rydstedt LL, Williams GH, Hollenberg NK. Renal
1992;71(1):169–180. system on essential hypertension in Kazakhs in and endocrine response to saline infusion in
50. Underwood PC, Chamarthi B, Williams JS, Vaidya A, Xinjiang. Clin Exp Hypertens. 2016;38(1):63–70. essential hypertension. Hypertension. 1986;8(3):
Garg R, Adler GK, Grotzke MP, Staskus G, 63. Purkait P, Halder K, Thakur S, Ghosh Roy A, 217–222.
Wadwekar D, Hopkins PN, Ferri C, McCall A, Raychaudhuri P, Bhattacharya S, Sarkar BN, Naidu 77. Seely EW, Moore TJ, Rogacz S, Gordon MS, Gleason
McClain D, Williams GH. Nonmodulation as the JM. Association of angiotensinogen gene SNPs and RE, Hollenberg NK, Williams GH. Angiotensin-
mechanism for salt sensitivity of blood pressure in mediated renin suppression is altered in non-
haplotypes with risk of hypertension in eastern
individuals with hypertension and type 2 diabetes modulating hypertension. Hypertension. 1989;
Indian population. Clin Hypertens. 2017;23(1):12.
mellitus. J Clin Endocrinol Metab. 2012;97(10): 13(1):31–37.
64. Zotova TY, Kubanova AP, Azova MM, Aissa AA,
3775–3782. 78. Rabinowe SL, Redgrave JE, Shoback DM, Podolsky S,
Gigani OO, Frolov VA. Analysis of polymorphism of
51. Underwood PC, Sun B, Williams JS, Pojoga LH, Raby Hollenberg NK, Williams GH. Renin suppression by
angiotensin system genes (ACE, AGTR1, and AGT)
B, Lasky-Su J, Hunt S, Hopkins PN, Jeunemaitre X, saline is blunted in nonmodulating essential hy-
and gene ITGB3 in patients with arterial hyper-
Adler GK, Williams GH. The association of the pertension. Hypertension. 1987;10(4):404–408.
tension in combination with metabolic syndrome.
angiotensinogen gene with insulin sensitivity in 79. Gordon MS, Steunkel CA, Conlin PR, Hollenberg
Bull Exp Biol Med. 2016;161(3):334–338.
humans: a tagging single nucleotide polymorphism NK, Williams GH. The role of dopamine in non-
65. Tsezou A, Karayannis G, Giannatou E, Papanikolaou
and haplotype approach. Metabolism. 2011;60(8): modulating hypertension. J Clin Endocrinol Metab.
V, Triposkiadis F. Association of renin-angiotensin
1150–1157. 1989;69(2):426–432.
system and natriuretic peptide receptor A gene
52. Dluhy RG, Smith K, Taylor T, Hollenberg NK, 80. Redgrave J, Canessa M, Gleason R, Hollenberg NK,
polymorphisms with hypertension in a Hellenic
Williams GH. Prolonged converting enzyme in- Williams GH. Red blood cell lithium-sodium
hibition in non-modulating hypertension. Hyper- population. J Renin Angiotensin Aldosterone Syst. countertransport in non-modulating essential hy-
tension. 1989;13(4):371–377. 2008;9(4):202–207. pertension. Hypertension. 1989;13(6 Pt 2):721–726.
53. Taylor T, Moore TJ, Hollenberg NK, Williams GH. 66. Kosachunhanun N, Hunt SC, Hopkins PN, Williams 81. Srikumar N, Brown NJ, Hopkins PN, Jeunemaitre X,
Converting-enzyme inhibition corrects the altered RR, Jeunemaitre X, Corvol P, Ferri C, Mortensen RM, Hunt SC, Vaughan DE, Williams GH. PAI-1 in hu-
adrenal response to angiotensin II in essential hy- Hollenberg NK, Williams GH. Genetic determinants man hypertension: relation to hypertensive groups.
pertension. Hypertension. 1984;6(1):92–99. of nonmodulating hypertension. Hypertension. Am J Hypertens. 2002;15(8):683–690.
54. Williams GH, Hollenberg NK. Non-modulating es- 2003;42(5):901–908. 82. Raji A, Williams GH, Jeunemaitre X, Hopkins PN,
sential hypertension: a subset particularly responsive 67. Kaplan İ, Sancaktar E, Ece A, Şen V, Tekkeşin N, Hunt SC, Hollenberg NK, Seely EW. Insulin re-
to converting enzyme inhibitors. J Hypertens Suppl. Basarali MK, Kelekci S, Evliyaoglu O. Gene poly- sistance in hypertensives: effect of salt sensitivity,
1985;3(2):S81–S87. morphisms of adducin GLY460TRP, ACE I/D, and renin status and sodium intake. J Hypertens. 2001;
55. Bonfim-Silva R, Guimarães LO, Souza Santos J, AGT M235T in pediatric hypertension patients. 19(1):99–105.
Pereira JF, Leal Barbosa AA, Souza Rios DL. Case- Med Sci Monit. 2014;20:1745–1750. 83. Fisher ND, Ferri C, Bellini C, Santucci A, Gleason R,
control association study of polymorphisms in the 68. Kolovou V, Lagou E, Mihas C, Vasiliki G, Katsiki N, Williams GH, Hollenberg NK, Seely EW. Age, gender,
angiotensinogen and angiotensin-converting en- Kollia A, Triposkiadis F, Degiannis D, Mavrogeni S, and non-modulation. A sexual dimorphism in es-
zyme genes and coronary artery disease and sys- Kolovou G. Angiotensinogen (AGT) M235T, AGT sential hypertension. Hypertension. 1997;29(4):
temic artery hypertension in African-Brazilians and T174M and angiotensin-1-converting enzyme 980–985.
Caucasian-Brazilians. J Genet. 2016;95(1):63–69. (ACE) I/D gene polymorphisms in essential hy- 84. Frazier L, Turner ST, Schwartz GL, Chapman AB,
56. Tabei SM, Nariman A, Daliri K, Roozbeh J, Khezri A, pertension: effects on ramipril efficacy. Open Boerwinkle E. Multilocus effects of the renin-
Goodarzi HR, Lotfi M, Sefidbakht S, Entezam M. Cardiovasc Med J. 2015;9(1):118–126. angiotensin-aldosterone system genes on blood
Simple renal cysts and hypertension are associated 69. Srivastava K, Chandra S, Bhatia J, Narang R, Saluja D. pressure response to a thiazide diuretic. Pharma-
with angiotensinogen (AGT) gene variant in Shiraz Association of angiotensinogen (M235T) gene cogenomics J. 2004;4(1):17–23.
population (Iran). J Renin Angiotensin Aldosterone polymorphism with blood pressure lowering re- 85. Hingorani AD, Jia H, Stevens PA, Hopper R,
Syst. 2015;16(2):409–414. sponse to angiotensin converting enzyme inhibitor Dickerson JE, Brown MJ. Renin-angiotensin system
57. Goldenberg I, Moss AJ, Ryan D, McNitt S, Eberly SW, (enalapril). J Pharm Pharm Sci. 2012;15(3):399–406. gene polymorphisms influence blood pressure and
Zareba W. Polymorphism in the angiotensinogen 70. Ramachandran V, Ismail P, Stanslas J, Shamsudin N. the response to angiotensin converting enzyme
gene, hypertension, and ethnic differences in the Analysis of renin-angiotensin aldosterone system inhibition. J Hypertens. 1995;13(12 Pt 2):1602–1609.
risk of recurrent coronary events. Hypertension. gene polymorphisms in Malaysian essential hy- 86. Dudley C, Keavney B, Casadei B, Conway J, Bird R,
2006;48(4):693–699. pertensive and type 2 diabetic subjects. Cardiovasc Ratcliffe P. Prediction of patient responses to an-
58. Afshariani R, Roozbeh J, Sharifian M, Ghaedi M, Diabetol. 2009;8(1):11. tihypertensive drugs using genetic polymorphisms:
Samsami Dehaghani A, Ghaderi A. Association 71. Liao X, Yang Z, Peng D, Dai H, Lei Y, Zhao Q, Han Y, investigation of renin-angiotensin system genes.
between angiotensinogen M235T polymorphism Wang W. Association of T174M polymorphism of J Hypertens. 1996;14(2):259–262.
REVIEW
87. Heidari F, Vasudevan R, Mohd Ali SZ, Ismail P, 101. Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn Righetti M, Rivera R, Stella P, Troffa C, Zagato L,
Arkani M. RAS genetic variants in interaction with ME, Karas RH. Striatin assembles a membrane Bianchi G. Polymorphisms of a-adducin and salt
ACE inhibitors drugs influences essential hyper- signaling complex necessary for rapid, nongenomic sensitivity in patients with essential hypertension.
tension control. Arch Med Res. 2017;48(1):88–95. activation of endothelial NO synthase by estrogen Lancet. 1997;349(9062):1353–1357.
88. Lynch AI, Arnett DK, Davis BR, Boerwinkle E, Ford receptor alpha. Proc Natl Acad Sci USA. 2004; 115. Sugimoto K, Hozawa A, Katsuya T, Matsubara M,
CE, Eckfeldt JH, Leiendecker-Foster C. Sex-specific 101(49):17126–17131. Ohkubo T, Tsuji I, Motone M, Higaki J, Hisamachi S,
effects of AGT-6 and ACE I/D on pulse pressure after 102. Coutinho P, Vega C, Pojoga LH, Rivera A, Prado GN, Imai Y, Ogihara T. Alpha-adducin Gly460Trp
6 months on antihypertensive treatment: the Yao TM, Adler G, Torres-Grajales M, Maldonado ER, polymorphism is associated with low renin hy-
GenHAT study. Ann Hum Genet. 2007;71(Pt 6): Ramos-Rivera A, Williams JS, Williams G, Romero JR. pertension in younger subjects in the Ohasama
735–745. Aldosterone’s rapid, nongenomic effects are me- study. J Hypertens. 2002;20(9):1779–1784.
89. Do AN, Irvin MR, Lynch AI, Claas SA, Boerwinkle E, diated by striatin: a modulator of aldosterone’s 116. Manunta P, Cusi D, Barlassina C, Righetti M, Lanzani
Davis BR, Ford CE, Eckfeldt JH, Tiwari HK, Limdi NA, effect on estrogen action. Endocrinology. 2014; C, D’Amico M, Buzzi L, Citterio L, Stella P, Rivera R,
Arnett DK. The effects of angiotensinogen gene 155(6):2233–2243. Bianchi G. a-Adducin polymorphisms and renal
polymorphisms on cardiovascular disease out- 103. Baudrand R, Pojoga L, Romero JR. Aldosterone’s sodium handling in essential hypertensive patients.
comes during antihypertensive treatment in the mechanism of action: genomic and nongenomic Kidney Int. 1998;53(6):1471–1478.
GenHAT study. Front Pharmacol. 2014;5:210. signaling. In: Singh AK, Williams GH, eds. Textbook 117. Grant FD, Romero JR, Jeunemaitre X, Hunt SC,
90. Catanzaro DF. Molecular biology of renin and of Nephro-Endocrinology, 2nd ed. San Diego, CA: Hopkins PN, Hollenberg NH, Williams GH. Low-
regulation of its gene. In: Singh AK, Williams GH, Academic; 2017:173–186. renin hypertension, altered sodium homeostasis,

eds. Textbook of Nephro-Endocrinology. San 104. Garza AE, Rariy CM, Sun B, Williams J, Lasky-Su J, and an a-adducin polymorphism. Hypertension.
Diego, CA: Academic; 2017:389–400. Baudrand R, Yao T, Moize B, Hafiz WM, Romero JR, 2002;39(2):191–196.
91. Carey MR, Padia SH. Physiology and regulation of Adler GK, Ferri C, Hopkins PN, Pojoga LH, Williams 118. Fisher ND, Hurwitz S, Jeunemaitre X, Hopkins PN,
the renin–angiotensin–aldosterone system. In: GH. Variants in striatin gene are associated with Hollenberg NK, Williams GH. Familial aggregation of
Singh AK, Williams GH, eds. Textbook of Nephro- salt-sensitive blood pressure in mice and humans. low-renin hypertension. Hypertension. 2002;39(4):
Endocrinology, 2nd ed. San Diego, CA: Academic; Hypertension. 2015;65(1):211–217. 914–918.
2017:1–23. 105. Gupta T, Connors M, Tan JW, Manosroi W, Ahmed 119. Zhang LN, Ji LD, Fei LJ, Yuan F, Zhang YM, Xu J.
92. Sun B, Williams JS, Pojoga L, Chamarthi B, Lasky-Su J, N, Ting PY, Garza AE, Romero JR, Hopkins PN, Association between polymorphisms of alpha-
Raby BA, Hopkins PN, Jeunemaitre X, Brown NJ, Williams JS, Williams GH. Striatin gene polymorphic adducin gene and essential hypertension in Chi-
Ferri C, Williams GH. Renin gene polymorphism: its variants are associated with salt sensitive blood nese population. BioMed Res Int. 2013;2013:451094.
relationship to hypertension, renin levels and vas- pressure in normotensives and hypertensives. Am J 120. Beeks E, van der Klauw MM, Kroon AA, Spiering W,
cular responses. J Renin Angiotensin Aldosterone Syst. Hypertens. 2017;31(1):124–131. Fuss-Lejeune MJ, de Leeuw PW. a-Adducin
106. Garza AE, Pojoga LH, Moize B, Hafiz WM, Opsasnick
2011;12(4):564–571. Gly460Trp polymorphism and renal hemodynamics
LA, Siddiqui WT, Horenstein M, Adler GK, Williams
93. Fu Y, Katsuya T, Asai T, Fukuda M, Inamoto N, in essential hypertension. Hypertension. 2004;44(4):
GH, Khalil RA. Critical role of striatin in blood
Iwashima Y, Sugimoto K, Rakugi H, Higaki J, Ogihara 419–423.
pressure and vascular responses to dietary sodium
T. Lack of correlation between Mbo I restriction 121. Wang L, Chen S, Zhao Q, Hixson JE, Rao DC, Jaquish
intake. Hypertension. 2015;66(3):674–680.
fragment length polymorphism of renin gene and CE, Huang J, Lu X, Chen J, Cao J, Li J, Li H, He J, Liu DP,
107. Pojoga LH, Coutinho P, Rivera A, Yao TM,
essential hypertension in Japanese. Hypertens Res. Gu D; GenSalt Collaborative Research Group. As-
Maldonado ER, Youte R, Adler GK, Williams J,
2001;24(3):295–298. sociation between genetic variants of the ADD1
Turchin A, Williams GH, Romero JR. Activation of
94. Park J, Song K, Jang Y, Kim Yoon S. A polymorphism and GNB3 genes and blood pressure response to
the mineralocorticoid receptor increases striatin
of the renin gene rs6682082 is associated with the cold pressor test in a Chinese Han population:
levels. Am J Hypertens. 2012;25(2):243–249.
essential hypertension risk and blood pressure levels the GenSalt Study. Hypertens Res. 2012;35(8):
108. Tripodi G, Piscone A, Borsani G, Tisminetzky S,
in Korean women. Yonsei Med J. 2015;56(1): 805–810.
Salardi S, Sidoli A, James P, Pongor S, Bianchi G,
227–234. 122. Morrison AC, Bray MS, Folsom AR, Boerwinkle E.
Baralle FE. Molecular cloning of an adducin-like
95. Mansego ML, Redon J, Marin R, González-Albert V, ADD1 460W allele associated with cardiovascular
protein: evidence of a polymorphism in the
Martin-Escudero JC, Fabia MJ, Martinez F, Chaves FJ. normotensive and hypertensive rats of the Milan disease in hypertensive individuals. Hypertension.
Renin polymorphisms and haplotypes are associ- strain. Biochem Biophys Res Commun. 1991;177(3): 2002;39(6):1053–1057.
ated with blood pressure levels and hypertension 939–947. 123. Wang L, Zheng B, Zhao H, Du P, Sun A, Hua K, Gao
risk in postmenopausal women. J Hypertens. 2008; 109. Bianchi G, Tripodi G, Casari G, Salardi S, Barber BR, Y. a-Adducin gene G614T polymorphisms in es-
26(2):230–237. Garcia R, Leoni P, Torielli L, Cusi D, Ferrandi M. Two sential hypertension patients with high low density
96. Ying CQ, Wang YH, Wu ZL, Fang MW, Wang J, Li point mutations within the adducin genes are in- lipoprotein (LDL) levels. Indian J Med Res. 2014;
YS, Zhang YH, Qiu CC. Association of the renin volved in blood pressure variation. Proc Natl Acad 139(2):273–278.
gene polymorphism, three angiotensinogen gene Sci USA. 1994;91(9):3999–4003. 124. Ishikawa K, Katsuya T, Sato N, Nakata Y, Takami S,
polymorphisms and the haplotypes with essential 110. Matsuoka Y, Li X, Bennett V. Adducin: structure, Takiuchi S, Fu Y, Higaki J, Ogihara T. No association
hypertension in the Mongolian population. Clin Exp function and regulation. Cell Mol Life Sci. 2000;57(6): between a-adducin 460 polymorphism and es-
Hypertens. 2010;32(5):293–300. 884–895. sential hypertension in a Japanese population. Am J
97. Afruza R, Islam LN, Banerjee S, Hassan MM, Suzuki F, 111. Gallardo G, Barowski J, Ravits J, Siddique T, Lingrel JB, Hypertens. 1998;11(4 Pt 1):502–506.
Nabi AN. Renin gene polymorphisms in bangla- Robertson J, Steen H, Bonni A. An a2-Na/K ATPase/ 125. Kamitani A, Wong ZY, Fraser R, Davies DL, Connor
deshi hypertensive population. J Genomics. 2014;2: a-adducin complex in astrocytes triggers non-cell JM, Foy CJ, Watt GC, Harrap SB. Human a-adducin
45–53. autonomous neurodegeneration. Nat Neurosci. gene, blood pressure, and sodium metabolism.
98. Ramkumar N, Stuart D, Rees S, Hoek AV, Sigmund 2014;17(12):1710–1719. Hypertension. 1998;32(1):138–143.
CD, Kohan DE. Collecting duct-specific knockout of 112. Torielli L, Tivodar S, Montella RC, Iacone R, Padoani 126. Kato N, Sugiyama T, Nabika T, Morita H, Kurihara H,
renin attenuates angiotensin II-induced hyperten- G, Tarsini P, Russo O, Sarnataro D, Strazzullo P, Yazaki Y, Yamori Y. Lack of association between
sion. Am J Physiol Renal Physiol. 2014;307(8): Ferrari P, Bianchi G, Zurzolo C. a-Adducin muta- the a-adducin locus and essential hypertension in
F931–F938. tions increase Na/K pump activity in renal cells by the Japanese population. Hypertension. 1998;31(3):
99. Castets F, Rakitina T, Gaillard S, Moqrich A, Mattei affecting constitutive endocytosis: implications for 730–733.
MG, Monneron A. Zinedin, SG2NA, and striatin are tubular Na reabsorption. Am J Physiol Renal Physiol. 127. Ramu P, Umamaheswaran G, Shewade DG,
calmodulin-binding, WD repeat proteins principally 2008;295(2):F478–F487. Swaminathan RP, Balachander J, Adithan C.
expressed in the brain. J Biol Chem. 2000;275(26): 113. Casari G, Barlassina C, Cusi D, Zagato L, Muirhead R, Gly460Trp polymorphism of the ADD1 gene and
19970–19977. Righetti M, Nembri P, Amar K, Gatti M, Macciardi F, essential hypertension in an Indian population: a
100. Ueda K, Lu Q, Baur W, Aronovitz MJ, Karas RH. Binelli G, Bianchi G. Association of the a-adducin meta-analysis on hypertension risk. Indian J Hum
Rapid estrogen receptor signaling mediates estrogen- locus with essential hypertension. Hypertension. Genet. 2010;16(1):8–15.
induced inhibition of vascular smooth muscle cell 1995;25(3):320–326. 128. Niu WQ, Zhang Y, Ji KD, Gao PJ, Zhu DL. Lack of
proliferation. Arterioscler Thromb Vasc Biol. 2013;33(8): 114. Cusi D, Barlassina C, Azzani T, Casari G, Citterio L, association between a-adducin G460W poly-
1837–1843. Devoto M, Glorioso N, Lanzani C, Manunta P, morphism and hypertension: evidence from a

REVIEW
case-control study and a meta-analysis. J Hum 144. Hindorff LA, Heckbert SR, Psaty BM, Lumley T, polymorphisms in a Taiwanese hypertensive pop-
Hypertens. 2010;24(7):467–474. Siscovick DS, Herrington DM, Edwards KL, Tracy RP. ulation. Mol Biol Rep. 2013;40(5):3705–3711.
129. Manunta P, Lavery G, Lanzani C, Braund PS, b2-Adrenergic receptor polymorphisms and de- 158. Bellili NM, Foucan L, Fumeron F, Mohammedi K,
Simonini M, Bodycote C, Zagato L, Delli Carpini S, terminants of cardiovascular risk: the Cardiovascular Travert F, Roussel R, Balkau B, Tichet J, Marre M.
Tantardini C, Brioni E, Bianchi G, Samani NJ. Health Study. Am J Hypertens. 2005;18(3):392–397. Associations of the 2344 T.C and the 3097 G.A
Physiological interaction between a-adducin 145. Atia AE, Norsidah K, Nor Zamzila A, Rafidah Hanim polymorphisms of CYP11B2 gene with hyperten-
and WNK1-NEDD4L pathways on sodium-related M, Samsul D, Aznan MA, Rashidah AR, Norlelawati sion, type 2 diabetes, and metabolic syndrome in a
blood pressure regulation. Hypertension. 2008;52(2): AT. Preliminary study on association of b2-adrenergic French population. Am J Hypertens. 2010;23(6):
366–372. receptor polymorphism with hypertension in hy- 660–667.
130. Tripodi G, Florio M, Ferrandi M, Modica R, Zimdahl pertensive subjects attending Balok Health Centre, 159. Munshi A, Sharma V, Kaul S, Rajeshwar K, Babu MS,
H, Hubner N, Ferrari P, Bianchi G. Effect of Add1 Kuantan. Med J Malaysia. 2012;67(1):25–30. Shafi G, Anila AN, Balakrishna N, Alladi S, Jyothy A.
gene transfer on blood pressure in reciprocal 146. Kumar R, Kohli S, Mishra A, Garg R, Alam P, Stobdan Association of the 2344C/T aldosterone synthase
congenic strains of Milan rats. Biochem Biophys Res T, Nejatizadeh A, Gupta M, Tyagi S, Pasha MA. (CYP11B2) gene variant with hypertension and
Commun. 2004;324(2):562–568. Interactions between the genes of vasodilatation stroke. J Neurol Sci. 2010;296(1–2):34–38.
131. Gupta S, Chattopadhyaya I, Agrawal BK, Sehajpal pathways influence blood pressure and nitric oxide 160. Li X, Xie P, He J, Cai H, Yang R, Zhang Q, Li B, Qi W,
PK, Goel RK. Correlation of renin angiotensin sys- level in hypertension. Am J Hypertens. 2015;28(2): Ma H. CYP11B2 gene polymorphism and essential
tem (RAS) candidate gene polymorphisms with 239–247. hypertension among Tibetan, Dongxiang and Han
response to ramipril in patients with essential hy- 147. Anthony EG, Richard E, Lipkowitz MS, Bhatnagar V. populations from northwest of China. Clin Exp

pertension. J Postgrad Med. 2015;61(1):21–26. Association of the ADRB2 (rs2053044) poly- Hypertens. 2016;38(4):375–380.
132. Choi HD, Suh JH, Lee JY, Bae SK, Kang HE, Lee MG, morphism and angiotensin-converting enzyme- 161. Sun J, Zhao M, Miao S, Xi B. Polymorphisms of
Shin WG. Effects of ACE and ADD1 gene poly- inhibitor blood pressure response in the African three genes (ACE, AGT and CYP11B2) in the renin-
morphisms on blood pressure response to hydro- American Study of Kidney Disease and Hyperten- angiotensin-aldosterone system are not associ-
chlorothiazide: a meta-analysis. Int J Clin Pharmacol sion. Pharmacogenet Genomics. 2015;25(9):444–449. ated with blood pressure salt sensitivity: a
Ther. 2013;51(9):718–724. 148. Baudrand R, Pojoga LH, Romero JR, Williams GH. systematic meta-analysis. Blood Press. 2016;25(2):
133. Manglik A, Kobilka B. The role of protein dynamics Aldosterone’s mechanism of action: roles of lysine- 117–122.
in GPCR function: insights from the b2AR and specific demethylase 1, caveolin and striatin. Curr 162. Zhang H, Li X, Zhou L, Zhang K, Zhang Q, Li J, Wang
rhodopsin. Curr Opin Cell Biol. 2014;27:136–143. Opin Nephrol Hypertens. 2014;23(1):32–37. N, Jin M, Wu N, Cong M, Qiu C. A novel haplotype
134. De Léan A, Racz K, McNicoll N, Desrosiers ML. 149. Konoshita T; Genomic Disease Outcome Consor- of low-frequency variants in the aldosterone syn-
Direct b-adrenergic stimulation of aldosterone tium (G-DOC) Study Investigators. Do genetic thase gene among northern Han Chinese with
secretion in cultured bovine adrenal subcapsular variants of the renin-angiotensin system predict essential hypertension. Medicine (Baltimore). 2017;
cells. Endocrinology. 1984;115(2):485–492. blood pressure response to renin-angiotensin 96(39):e8150.
135. Pratt JH, McAteer JA. Beta-adrenergic enhancement system–blocking drugs?: a systematic review of 163. Todkar A, Di Chiara M, Loffing-Cueni D, Bettoni C,
of angiotensin II-stimulated aldosterone secretion. pharmacogenomics in the renin-angiotensin sys- Mohaupt M, Loffing J, Wagner CA. Aldosterone
Life Sci. 1989;44(26):2089–2095. tem. Curr Hypertens Rep. 2011;13(5):356–361. deficiency adversely affects pregnancy outcome in
136. Svetkey LP, Chen YT, McKeown SP, Preis L, Wilson 150. Iwai N, Kajimoto K, Tomoike H, Takashima N. mice. Pflugers Arch. 2012;464(4):331–343.
AF. Preliminary evidence of linkage of salt sensitivity Polymorphism of CYP11B2 determines salt sensi- 164. Lee G, Makhanova N, Caron K, Lopez ML, Gomez
in black Americans at the b2-adrenergic receptor tivity in Japanese. Hypertension. 2007;49(4):825–831. RA, Smithies O, Kim HS. Homeostatic responses in
locus. Hypertension. 1997;29(4):918–922. 151. Rossi E, Regolisti G, Perazzoli F, Negro A, Davoli S, the adrenal cortex to the absence of aldosterone in
137. Sun B, Williams JS, Svetkey LP, Kolatkar NS, Conlin Nicoli D, Sani C, Casali B. -344C/T polymorphism of mice. Endocrinology. 2005;146(6):2650–2656.
PR. b2-Adrenergic receptor genotype affects the CYP11B2 gene in Italian patients with idiopathic 165. Fontana V, de Faria AP, Barbaro NR, Sabbatini AR,
renin-angiotensin-aldosterone system response to low renin hypertension. Am J Hypertens. 2001;14(9 Modolo R, Lacchini R, Moreno H. Modulation of
the Dietary Approaches to Stop Hypertension Pt 1):934–941. aldosterone levels by 2344 C/T CYP11B2 poly-
(DASH) dietary pattern. Am J Clin Nutr. 2010;92(2): 152. Cun Y, Li J, Tang W, Sheng X, Yu H, Zheng B, Xiao C. morphism and spironolactone use in resistant
444–449. Association of WNK1 exon 1 polymorphisms with hypertension. J Am Soc Hypertens. 2014;8(3):
138. Komara M, Vasudevan R, Ismail P, Bakar SA, Pishva essential hypertension in Hani and Yi minorities of 146–151.
SR, Heidari F. Association of b2 adrenoceptor gene China. J Genet Genomics. 2011;38(4):165–171. 166. Rainey WE, Nakamura Y. Regulation of the adrenal
polymorphisms in Malaysian hypertensive subjects. 153. Nejatizadeh A, Kumar R, Stobdan T, Goyal AK, androgen biosynthesis. J Steroid Biochem Mol Biol.
Genet Mol Res. 2014;13(2):2939–2948. Gupta M, Tyagi S, Jain SK, Pasha MA. CYP11B2 gene 2008;108(3–5):281–286.
139. Liu Z, Qi H, Liu B, Liu K, Wu J, Cao H, Zhang J, Yan Y, haplotypes independently and in concurrence with 167. Baker ME, Nelson DR, Studer RA. Origin of the
He Y, Zhang L. Genetic susceptibility to salt- aldosterone and aldosterone to renin ratio increase response to adrenal and sex steroids: roles of
sensitive hypertension in a Han Chinese pop- the risk of hypertension. Clin Biochem. 2010;43(1–2): promiscuity and co-evolution of enzymes and
ulation: a validation study of candidate genes. 136–141. steroid receptors. J Steroid Biochem Mol Biol. 2015;
Hypertens Res. 2017;40(10):876–884. 154. Vamsi UM, Swapna N, Padma G, Vishnupriya S, 151:12–24.
140. Thomsen M, Dahl M, Tybjaerg-Hansen A, Padma T. Haplotype association and synergistic 168. Newton-Cheh C, Johnson T, Gateva V, Tobin MD,
Nordestgaard BG. b2-Adrenergic receptor Thr164IIe effect of human aldosterone synthase (CYP11B2) Bochud M, Coin L, Najjar SS, Zhao JH, Heath SC,
polymorphism, blood pressure and ischaemic heart gene polymorphisms causing susceptibility to es- Eyheramendy S, Papadakis K, Voight BF, Scott LJ,
disease in 66 750 individuals. J Intern Med. 2012; sential hypertension in Indian patients. Clin Exp Zhang F, Farrall M, Tanaka T, Wallace C, Chambers
271(3):305–314. Hypertens. 2016;38(8):659–665. JC, Khaw KT, Nilsson P, van der Harst P, Polidoro S,
141. Kawaguchi H, Masuo K, Katsuya T, Sugimoto K, 155. Bogacz A, Bartkowiak-Wieczorek J, Procyk D, Grobbee DE, Onland-Moret NC, Bots ML, Wain LV,
Rakugi H, Ogihara T, Tuck ML. b2- and b3-Adre- Seremak-Mrozikiewicz A, Majchrzycki M, Dziekan K, Elliott KS, Teumer A, Luan J, Lucas G, Kuusisto J,
noceptor polymorphisms relate to subsequent Bienert A, Czerny B. Analysis of the gene poly- Burton PR, Hadley D, McArdle WL, Brown M,
weight gain and blood pressure elevation in obese morphism of aldosterone synthase (CYP11B2) and Dominiczak A, Newhouse SJ, Samani NJ, Webster J,
normotensive individuals. Hypertens Res. 2006; atrial natriuretic peptide (ANP) in women with Zeggini E, Beckmann JS, Bergmann S, Lim N, Song K,
29(12):951–959. preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2016; Vollenweider P, Waeber G, Waterworth DM, Yuan
142. Masuo K, Katsuya T, Fu Y, Rakugi H, Ogihara T, Tuck 197:11–15. X, Groop L, Orho-Melander M, Allione A, Di
ML. b2- and b3-Adrenergic receptor poly- 156. Hsiao CF, Sheu WW, Hung YJ, Lin MW, Curb D, Gregorio A, Guarrera S, Panico S, Ricceri F,
morphisms are related to the onset of weight gain Ranadex K, Quertermous T, Chen YM, Chen IY, Wu Romanazzi V, Sacerdote C, Vineis P, Barroso I,
and blood pressure elevation over 5 years. Circu- KD. The effects of the renin-angiotensin- Sandhu MS, Luben RN, Crawford GJ, Jousilahti P,
lation. 2005;111(25):3429–3434. aldosterone system gene polymorphisms on in- Perola M, Boehnke M, Bonnycastle LL, Collins FS,
143. Vardeny O, Peppard PE, Finn LA, Faraco JH, Mignot sulin resistance in hypertensive families. J Renin Jackson AU, Mohlke KL, Stringham HM, Valle TT,
E, Hla KM. b2 Adrenergic receptor polymorphisms Angiotensin Aldosterone Syst. 2012;13(4):446–454. Willer CJ, Bergman RN, Morken MA, Döring A,
and nocturnal blood pressure dipping status in the 157. Sia SK, Chiou HL, Chen SC, Tsai CF, Yang SF, Ueng Gieger C, Illig T, Meitinger T, Org E, Pfeufer A,
Wisconsin Sleep Cohort Study. J Am Soc Hypertens. KC. Distribution and phenotypic expression of Wichmann HE, Kathiresan S, Marrugat J, O’Donnell
2011;5(2):114–122. mineralocorticoid receptor and CYP11B2 T-344C CJ, Schwartz SM, Siscovick DS, Subirana I, Freimer
REVIEW
NB, Hartikainen AL, McCarthy MI, O’Reilly PF, angiotensin–aldosterone system. Cardiovasc Res. 191. Cooke PS, Nanjappa MK, Ko C, Prins GS, Hess RA.
Peltonen L, Pouta A, de Jong PE, Snieder H, van Gilst 1999;43(2):300–307. Estrogens in male physiology. Physiol Rev. 2017;
WH, Clarke R, Goel A, Hamsten A, Peden JF, Seedorf 177. Greenberg BH. Endothelin and endothelin receptor 97(3):995–1043.
U, Syvänen AC, Tognoni G, Lakatta EG, Sanna S, antagonists in heart failure. Congest Heart Fail. 2002; 192. Peter I, Shearman AM, Zucker DR, Schmid CH,
Scheet P, Schlessinger D, Scuteri A, Dörr M, Ernst F, 8(5):257–261. Demissie S, Cupples LA, Larson MG, Vasan RS,
Felix SB, Homuth G, Lorbeer R, Reffelmann T, Rettig 178. Asai T, Ohkubo T, Katsuya T, Higaki J, Fu Y, Fukuda D’Agostino RB, Karas RH, Mendelsohn ME,
R, Völker U, Galan P, Gut IG, Hercberg S, Lathrop M, Hozawa A, Matsubara M, Kitaoka H, Tsuji I, Araki Housman DE, Levy D. Variation in estrogen-related
GM, Zelenika D, Deloukas P, Soranzo N, Williams T, Satoh H, Hisamichi S, Imai Y, Ogihara T. genes and cross-sectional and longitudinal blood
FM, Zhai G, Salomaa V, Laakso M, Elosua R, Forouhi Endothelin-1 gene variant associates with blood pressure in the Framingham Heart Study.
NG, Völzke H, Uiterwaal CS, van der Schouw YT, pressure in obese Japanese subjects: the Ohasama J Hypertens. 2005;23(12):2193–2200.
Numans ME, Matullo G, Navis G, Berglund G, Study. Hypertension. 2001;38(6):1321–1324. 193. Chen C, Li Y, Chen F, Pan H, Shen H, Sun Z, Wu Y,
Bingham SA, Kooner JS, Connell JM, Bandinelli S, 179. Letizia C, Cerci S, De Toma G, D’Ambrosio C, De Zhou J, Ba L, Zhao J. Estrogen receptor beta genetic
Ferrucci L, Watkins H, Spector TD, Tuomilehto J, Ciocchis A, Coassin S, Scavo D. High plasma variants and combined oral contraceptive use as
Altshuler D, Strachan DP, Laan M, Meneton P, endothelin-1 levels in hypertensive patients with relates to the risk of hypertension in Chinese
Wareham NJ, Uda M, Jarvelin MR, Mooser V, low-renin essential hypertension. J Hum Hypertens. women. Arch Med Res. 2010;41(8):599–605.
Melander O, Loos RJ, Elliott P, Abecasis GR, Caulfield 1997;11(7):447–451. 194. Manosroi W, Tan JW, Rariy CM, Sun B, Goodarzi
M, Munroe PB; Wellcome Trust Case Control 180. Tan JW, Gupta T, Manosroi W, Yao TM, Hopkins MO, Saxena AR, Williams JS, Pojoga LH, Lasky-Su J,
Consortium. Genome-wide association study Cui J, Guo X, Taylor KD, Chen YI, Xiang AH, Hsueh

PN, Williams JS, Adler GK, Romero JR, Williams GH.
identifies eight loci associated with blood pressure. Dysregulated aldosterone secretion in persons of WA, Raffel LJ, Buchanan TA, Rotter JI, Williams GH,
Nat Genet. 2009;41(6):666–676. African descent with endothelin-1 gene variants. JCI Seely EW. The association of estrogen receptor-b
169. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Insight. 2017;2(23):95992. gene variation with salt-sensitive blood pressure.
Dehghan A, Glazer NL, Morrison AC, Johnson AD, 181. Panoulas VF, Douglas KM, Smith JP, Taffé P, J Clin Endocrinol Metab. 2017;102(11):4124–4135.
Aspelund T, Aulchenko Y, Lumley T, Köttgen A, Stavropoulos-Kalinoglou A, Toms TE, Elisaf MS, 195. Iwai N, Tago N, Yasui N, Kokubo Y, Inamoto N,
Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Nightingale P, Kitas GD. Polymorphisms of the Tomoike H, Shioji K. Genetic analysis of 22 can-
Arking DE, Mitchell GF, Mattace-Raso FU, Smith endothelin-1 gene associate with hypertension in didate genes for hypertension in the Japanese
AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, patients with rheumatoid arthritis. Endothelium. population. J Hypertens. 2004;22(6):1119–1126.
Harris TB, Ganesh SK, O’Donnell CJ, Hofman A, 2008;15(4):203–212. 196. Zhu Y, Bian Z, Lu P, Karas RH, Bao L, Cox D, Hodgin J,
Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, 182. Tiret L, Poirier O, Hallet V, McDonagh TA, Morrison Shaul PW, Thoren P, Smithies O, Gustafsson JA,
Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang C, McMurray JJ, Dargie HJ, Arveiler D, Ruidavets JB, Mendelsohn ME. Abnormal vascular function and
TJ, Gudnason V, Larson MG, Chakravarti A, Psaty Luc G, Evans A, Cambien F. The Lys198Asn poly- hypertension in mice deficient in estrogen
BM, van Duijn CM. Genome-wide association study receptorb. Science. 2002;295(5554):505–508.
morphism in the endothelin-1 gene is associated
of blood pressure and hypertension. Nat Genet. 197. Arias-Loza PA, Hu K, Dienesch C, Mehlich AM,
with blood pressure in overweight people. Hyper-
2009;41(6):677–687. König S, Jazbutyte V, Neyses L, Hegele-Hartung C,
tension. 1999;33(5):1169–1174.
170. Tabara Y, Kohara K, Kita Y, Hirawa N, Katsuya T, Heinrich Fritzemeier K, Pelzer T. Both estrogen
183. Aggarwal PK, Jain V, Srinivasan R, Jha V. Maternal
Ohkubo T, Hiura Y, Tajima A, Morisaki T, Miyata T, receptor subtypes, a and b, attenuate cardiovas-
EDN1 G5665T polymorphism influences circulating
Nakayama T, Takashima N, Nakura J, Kawamoto R, cular remodeling in aldosterone salt-treated rats.
endothelin-1 levels and plays a role in determina-
Takahashi N, Hata A, Soma M, Imai Y, Kokubo Y, Hypertension. 2007;50(2):432–438.
tion of preeclampsia phenotype. J Hypertens. 2009;
Okamura T, Tomoike H, Iwai N, Ogihara T, Inoue I, 198. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR,
27(10):2044–2050.
Tokunaga K, Johnson T, Caulfield M, Munroe P, Cole PA, Casero RA, Shi Y. Histone demethylation
184. Fang Z, Li M, Ma Z, Tu G. Association of endothelin-
Umemura S, Ueshima H, Miki T; Global Blood mediated by the nuclear amine oxidase homolog
1 gene polymorphisms with essential hypertension
Pressure Genetics Consortium. Common variants in LSD1. Cell. 2004;119(7):941–953.
in a Chinese population. Genet Mol Res. 2017;16(3).
the ATP2B1 gene are associated with susceptibility 199. Lan F, Nottke AC, Shi Y. Mechanisms involved in
185. Ahmed M, Rghigh A. Polymorphism in endothelin-
to hypertension: the Japanese Millennium Genome the regulation of histone lysine demethylases. Curr
1 gene: an overview. Curr Clin Pharmacol. 2016;
Project. Hypertension. 2010;56(5):973–980. Opin Cell Biol. 2008;20(3):316–325.
11(3):191–210. 200. Williams JS, Chamarthi B, Goodarzi MO, Pojoga LH,
171. Liu C, Li H, Qi Q, Lu L, Gan W, Loos RJ, Lin X.
186. Banno M, Hanada H, Kamide K, Kokubo Y, Kada A,
Common variants in or near FGF5, CYP17A1 and Sun B, Garza AE, Raby BA, Adler GK, Hopkins PN,
Yang J, Tanaka C, Takiuchi S, Horio T, Matayoshi T, Brown NJ, Jeunemaitre X, Ferri C, Fang R, Leonor T,
MTHFR genes are associated with blood pressure
Yasuda H, Nagura J, Tomoike H, Kawano Y, Miyata Cui J, Guo X, Taylor KD, Ida Chen YD, Xiang A, Raffel
and hypertension in Chinese Hans. J Hypertens.
2011;29(1):70–75. T. Association of genetic polymorphisms of LJ, Buchanan TA, Rotter JI, Williams GH, Shi Y.
172. Li X, Ling Y, Lu D, Lu Z, Liu Y, Chen H, Gao X. endothelin-converting enzyme-1 gene with hy- Lysine-specific demethylase 1: an epigenetic regu-
Common polymorphism rs11191548 near the pertension in a Japanese population and rare lator of salt-sensitive hypertension. Am J Hypertens.
CYP17A1 gene is associated with hypertension and missense mutation in preproendothelin-1 in Japa- 2012;25(7):812–817.
systolic blood pressure in the Han Chinese pop- nese hypertensives. Hypertens Res. 2007;30(6): 201. Krug AW, Tille E, Sun B, Pojoga L, Williams J,
ulation. Am J Hypertens. 2013;26(4):465–472. 513–520. Chamarthi B, Lichtman AH, Hopkins PN, Adler GK,
173. Lin Y, Lai X, Chen B, Xu Y, Huang B, Chen Z, Zhu S, 187. Ikeda T, Ohta H, Okada M, Kawai N, Nakao R, Siegl Williams GH. Lysine-specific demethylase-1 mod-
Yao J, Jiang Q, Huang H, Wen J, Chen G. Genetic PK, Kobayashi T, Maeda S, Miyauchi T, Nishikibe M. ifies the age effect on blood pressure sensitivity to
variations in CYP17A1, CACNB2 and PLEKHA7 are Pathophysiological roles of endothelin-1 in Dahl dietary salt intake. Age (Dordr). 2013;35(5):
associated with blood pressure and/or hypertension salt-sensitive hypertension. Hypertension. 1999; 1809–1820.
in She ethnic minority of China. Atherosclerosis. 34(3):514–519. 202. Pojoga LH, Williams JS, Yao TM, Kumar A, Raffetto
2011;219(2):709–714. 188. Rothermund L, Luckert S, Kossmehl P, Paul M, JD, do Nascimento GR, Reslan OM, Adler GK,
174. Xi B, Shen Y, Zhao X, Chandak GR, Cheng H, Hou D, Kreutz R. Renal endothelin ETA/ETB receptor im- Williams GH, Shi Y, Khalil RA. Histone demethylase
Li Y, Ott J, Zhang Y, Wang X, Mi J. Association of balance differentiates salt-sensitive from salt- LSD1 deficiency during high-salt diet is associ-
common variants in/near six genes (ATP2B1, CSK, resistant spontaneous hypertension. Hypertension. ated with enhanced vascular contraction, altered
MTHFR, CYP17A1, STK39 and FGF5) with blood 2001;37(2):275–280. NO-cGMP relaxation pathway, and hypertension.
pressure/hypertension risk in Chinese children. 189. Kisanuki YY, Emoto N, Ohuchi T, Widyantoro B, Am J Physiol Heart Circ Physiol. 2011;301(5):
J Hum Hypertens. 2014;28(1):32–36. Yagi K, Nakayama K, Kedzierski RM, Hammer RE, H1862–H1871.
175. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Yanagisawa H, Williams SC, Richardson JA, Suzuki T, 203. Chen SY, Bhargava A, Mastroberardino L, Meijer
Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. Yanagisawa M. Low blood pressure in endothelial OC, Wang J, Buse P, Firestone GL, Verrey F, Pearce D.
A novel potent vasoconstrictor peptide produced cell–specific endothelin 1 knockout mice. Hyper- Epithelial sodium channel regulated by aldosterone-
by vascular endothelial cells. Nature. 1988;332(6163): tension. 2010;56(1):121–128. induced protein sgk. Proc Natl Acad Sci USA. 1999;
411–415. 190. Imamov O, Shim GJ, Warner M, Gustafsson JA. 96(5):2514–2519.
176. Rossi GP, Sacchetto A, Cesari M, Pessina AC. In- Estrogen receptor b in health and disease. Biol 204. Lang F, Böhmer C, Palmada M, Seebohm G, Strutz-
teractions between endothelin-1 and the renin– Reprod. 2005;73(5):866–871. Seebohm N, Vallon V. (Patho)physiological significance

REVIEW
of the serum- and glucocorticoid-inducible kinase adducin-1 polymorphisms in women with pre- sensitivity of blood pressure is associated with
isoforms. Physiol Rev. 2006;86(4):1151–1178. eclampsia and gestational hypertension. Reprod Sci. polymorphisms in the sodium-bicarbonate cotrans-
205. Lou Y, Zhang F, Luo Y, Wang L, Huang S, Jin F. Serum 2009;16(9):819–826. porter. Hypertension. 2012;60(5):1359–1366.
and glucocorticoid regulated kinase 1 in sodium 220. Miao HW, Gong H. Correlation of ACE gene 234. Barkley RA, Chakravarti A, Cooper RS, Ellison RC,
homeostasis. Int J Mol Sci. 2016;17(8):E1307. deletion/insertion polymorphism and risk of Hunt SC, Province MA, Turner ST, Weder AB,
206. Rao AD, Sun B, Saxena A, Hopkins PN, Jeunemaitre pregnancy-induced hypertension: a meta-analysis Boerwinkle E; Family Blood Pressure Program. Po-
X, Brown NJ, Adler GK, Williams JS. Polymorphisms based on 10,236 subjects. J Renin Angiotensin Al- sitional identification of hypertension susceptibility
in the serum- and glucocorticoid-inducible kinase 1 dosterone Syst. 2015;16(4):982–994. genes on chromosome 2. Hypertension. 2004;43(2):
gene are associated with blood pressure and renin 221. He J, Bian Y, Gao F, Li M, Qiu L, Wu W, Zhou H, Liu 477–482.
response to dietary salt intake. J Hum Hypertens. G, Xiao C. RNA interference targeting the ACE gene 235. Wen D, Yuan Y, Warner PC, Wang B, Cornelius RJ,
2013;27(3):176–180. reduced blood pressure and improved myocardial Wang-France J, Li H, Boettger T, Sansom SC.
207. Zhang D, Gu D, He J, Hixson JE, Rao DC, Li C, He H, remodelling in SHRs. Clin Sci (Lond). 2009;116(3): Increased epithelial sodium channel activity con-
Chen J, Huang J, Chen J, Rice TK, Chen S, Kelly TN. 249–255. tributes to hypertension caused by Na1-HCO2 3
Associations of the serum/glucocorticoid regulated 222. Heidari F, Vasudevan R, Mohd Ali SZ, Ismail P, cotransporter electrogenic 2 deficiency. Hyperten-
kinase genes with BP changes and hypertension Etemad A, Pishva SR, Othman F, Abu Bakar S. sion. 2015;66(1):68–74.
incidence: the Gensalt Study. Am J Hypertens. 2017; Association of insertion/deletion polymorphism of 236. Hirawa N, Fujiwara A, Umemura S. ATP2B1 and
30(1):95–101. angiotensin-converting enzyme gene among Malay blood pressure: from associations to pathophysi-
208. Chu C, Wang Y, Wang M, Mu JJ, Liu FQ, Wang L, Ren male hypertensive subjects in response to ACE ology. Curr Opin Nephrol Hypertens. 2013;22(2):

KY, Wang D, Yuan ZY. Common variants in serum/ inhibitors. J Renin Angiotensin Aldosterone Syst. 2015; 177–184.
glucocorticoid regulated kinase 1 (SGK1) and blood 16(4):872–879. 237. Lee S, Kim SH, Shin C. Interaction according to
pressure responses to dietary sodium or potassium 223. Katori M, Majima M. Pivotal role of renal kallikrein- urinary sodium excretion level on the association
interventions: a family-based association study. kinin system in the development of hypertension between ATP2B1 rs17249754 and incident hyper-
Kidney Blood Press Res. 2015;40(4):424–434. and approaches to new drugs based on this re- tension: the Korean genome epidemiology study.
209. Wulff P, Vallon V, Huang DY, Völkl H, Yu F, Richter lationship. Jpn J Pharmacol. 1996;70(2):95–128. Clin Exp Hypertens. 2016;38(4):352–358.
K, Jansen M, Schlünz M, Klingel K, Loffing J, 224. Braun A, Maier E, Kammerer S, Müller B, Roscher 238. Xu J, Qian HX, Hu SP, Liu LY, Zhou M, Feng M, Su J, Ji
Kauselmann G, Bösl MR, Lang F, Kuhl D. Impaired AA. A novel sequence polymorphism in the pro- LD. Gender-specific association of ATP2B1 variants
renal Na1 retention in the sgk1-knockout mouse. moter region of the human B2-bradykinin receptor with susceptibility to essential hypertension in the
J Clin Invest. 2002;110(9):1263–1268. gene. Hum Genet. 1996;97(5):688–689. Han Chinese population. BioMed Res Int. 2016;2016:
210. De Mello WC. Local renin angiotensin aldosterone 225. Gu D, Zhao Q, Kelly TN, Hixson JE, Rao DC, Cao J, 1910565.
systems and cardiovascular diseases. Med Clin North Chen J, Li J, Chen J, Ji X, Hu D, Wang X, Liu DP, He J. 239. Wang Y, Zhang Y, Li Y, Zhou X, Wang X, Gao P, Jin L,
Am. 2017;101(1):117–127. The role of the kallikrein-kinin system genes in the Zhang X, Zhu D. Common variants in the ATP2B1
211. Song GG, Bae SC, Kim JH, Lee YH. The angiotensin- salt sensitivity of blood pressure: the GenSalt Study. gene are associated with hypertension and arterial
converting enzyme insertion/deletion polymorphism Am J Epidemiol. 2012;176(Suppl 7):S72–S80. stiffness in Chinese population. Mol Biol Rep. 2013;
and susceptibility to rheumatoid arthritis, vitiligo and 226. Gainer JV, Brown NJ, Bachvarova M, Bastien L, 40(2):1867–1873.
psoriasis: a meta-analysis. J Renin Angiotensin Aldoste- Maltais I, Marceau F, Bachvarov DR. Altered fre- 240. Shin YB, Lim JE, Ji SM, Lee HJ, Park SY, Hong KW, Lim
rone Syst. 2015;16(1):195–202. quency of a promoter polymorphism of the kinin M, McCarthy MI, Lee YH, Oh B. Silencing of Atp2b1
212. Hollenberg NK, Williams GH. The renal response to B2 receptor gene in hypertensive African-Americans. increases blood pressure through vasoconstriction.
converting enzyme inhibition and the treatment of Am J Hypertens. 2000;13(12):1268–1273. J Hypertens. 2013;31(8):1575–1583.
sodium-sensitive hypertension. Clin Exp Hypertens 227. Bhupatiraju C, Patkar S, Pandharpurkar D, Joshi S, 241. Fujiwara A, Hirawa N, Fujita M, Kobayashi Y,
A. 1987;9(2–3):531–541. Tirunilai P. Association and interaction of 258C.T Okuyama Y, Yatsu K, Katsumata M, Yamamoto Y,
213. Bavishi C, Bangalore S, Messerli FH. Renin angio- and 69 bp polymorphisms of BDKRB2 gene causing Ichihara N, Saka S, Toya Y, Yasuda G, Goshima Y,
tensin aldosterone system inhibitors in hyperten- susceptibility to essential hypertension. Clin Exp Tabara Y, Miki T, Ueshima H, Ishikawa Y, Umemura
sion: is there evidence for benefit independent of Hypertens. 2012;34(3):230–235. S. Impaired nitric oxide production and increased
blood pressure reduction? Prog Cardiovasc Dis. 2016; 228. Fu Y, Katsuya T, Matsuo A, Yamamoto K, Akasaka blood pressure in systemic heterozygous ATP2B1
59(3):253–261. H, Takami Y, Iwashima Y, Sugimoto K, Ishikawa K, null mice. J Hypertens. 2014;32(7):1415–1423.
214. Wong PY, Talamo RC, Williams GH, Colman RW. Ohishi M, Rakugi H, Ogihara T. Relationship of 242. Kobayashi Y, Hirawa N, Tabara Y, Muraoka H, Fujita
Response of the kallikrein-kinin and renin-angiotensin bradykinin B2 receptor gene polymorphism with M, Miyazaki N, Fujiwara A, Ichikawa Y, Yamamoto
systems to saline infusion and upright posture. J Clin essential hypertension and left ventricular hyper- Y, Ichihara N, Saka S, Wakui H, Yoshida S, Yatsu K,
Invest. 1975;55(4):691–698. trophy. Hypertens Res. 2004;27(12):933–938. Toya Y, Yasuda G, Kohara K, Kita Y, Takei K,
215. Zhang L, Miyaki K, Araki J, Song Y, Kimura T, Omae 229. Kopkan L, Husková Z, Jı́chová Š, Červenková L, Goshima Y, Ishikawa Y, Ueshima H, Miki T,
K,Muramatsu M. Interaction of angiotensin Červenka L, Saifudeen Z, El-Dahr SS. Conditional Umemura S. Mice lacking hypertension candidate
I-converting enzyme insertion-deletion polymorphism knockout of collecting duct bradykinin B2 receptors gene ATP2B1 in vascular smooth muscle cells show
and daily salt intake influences hypertension in Japa- exacerbates angiotensin II-induced hypertension significant blood pressure elevation. Hypertension.
nese men. Hypertens Res. 2006;29(10):751–758. during high salt intake. Clin Exp Hypertens. 2016; 2012;59(4):854–860.
216. Das M, Pal S, Ghosh A. Angiotensin converting 38(1):1–9. 243. Wang Y, O’Connell JR, McArdle PF, Wade JB, Dorff
enzyme gene polymorphism (insertion/deletion) 230. Virkki LV, Wilson DA, Vaughan-Jones RD, Boron WF. SE, Shah SJ, Shi X, Pan L, Rampersaud E, Shen H, Kim
and hypertension in adult Asian Indians: a Functional characterization of human NBC4 as an JD, Subramanya AR, Steinle NI, Parsa A, Ober CC,
population-based study from Calcutta, India. Hum electrogenic Na1-HCO2 3 cotransporter (NBCe2). Welling PA, Chakravarti A, Weder AB, Cooper RS,
Biol. 2008;80(3):303–312. Am J Physiol Cell Physiol. 2002;282(6):C1278–C1289. Mitchell BD, Shuldiner AR, Chang YP. Whole-
217. Caprioli J, Mele C, Mossali C, Gallizioli L, Giacchetti 231. Sassani P, Pushkin A, Gross E, Gomer A, Abuladze N, genome association study identifies STK39 as a
G, Noris M, Remuzzi G, Benigni A. Polymorphisms Dukkipati R, Carpenito G, Kurtz I. Functional hypertension susceptibility gene. Proc Natl Acad Sci
of EDNRB, ATG, and ACE genes in salt-sensitive characterization of NBC4: a new electrogenic USA. 2009;106(1):226–231.
hypertension. Can J Physiol Pharmacol. 2008;86(8): sodium-bicarbonate cotransporter. Am J Physiol Cell 244. Delpire E, Gagnon KB. SPAK and OSR1: STE20 ki-
505–510. Physiol. 2002;282(2):C408–C416. nases involved in the regulation of ion homoeo-
218. Ramachandran V, Ismail P, Stanslas J, Shamsudin N, 232. Gildea JJ, Xu P, Kemp BA, Carlson JM, Tran HT, Bigler stasis and volume control in mammalian cells.
Moin S, Mohd Jas R. Association of insertion/ Wang D, Langouët-Astrié CJ, McGrath HE, Carey Biochem J. 2008;409(2):321–331.
deletion polymorphism of angiotensin-converting RM, Jose PA, Felder RA. Sodium bicarbonate 245. Moriguchi T, Urushiyama S, Hisamoto N, Iemura S,
enzyme gene with essential hypertension and type cotransporter NBCe2 gene variants increase sodium Uchida S, Natsume T, Matsumoto K, Shibuya H.
2 diabetes mellitus in Malaysian subjects. J Renin and bicarbonate transport in human renal proximal WNK1 regulates phosphorylation of cation-chloride-
Angiotensin Aldosterone Syst. 2008;9(4):208–214. tubule cells. PLoS One. 2018;13(4):e0189464. coupled cotransporters via the STE20-related kinases,
219. Mandò C, Antonazzo P, Tabano S, Zanutto S, Pileri 233. Carey RM, Schoeffel CD, Gildea JJ, Jones JE, McGrath SPAK and OSR1. J Biol Chem. 2005;280(52):
P, Somigliana E, Colleoni F, Martinelli A, Zolin A, HE, Gordon LN, Park MJ, Sobota RS, Underwood PC, 42685–42693.
Benedetto C, Marozio L, Neri I, Facchinetti F, Miozzo Williams J, Sun B, Raby B, Lasky-Su J, Hopkins PN, 246. Rhee MY, Yang SJ, Oh SW, Park Y, Kim CI, Park HK,
M, Cetin I. Angiotensin-converting enzyme and Adler GK, Williams SM, Jose PA, Felder RA. Salt Park Cy. Novel genetic variations associated with
REVIEW
salt sensitivity in the Korean population. Hypertens targets for therapeutic intervention. Proc Natl Acad Japanese population. Circulation. 2010;121(21):
Res. 2011;34(5):606–611. Sci USA. 2003;100(24):14109–14114. 2302–2309.
247. Persu A, Evenepoel L, Jin Y, Mendola A, Ngueta G, 260. Turner ST, Schwartz GL, Chapman AB, Boerwinkle E. 274. Niu W, Zhang Y, Ji K, Gu M, Gao P, Zhu D.
Yang WY, Gruson D, Horman S, Staessen JA, Vikkula WNK1 kinase polymorphism and blood pressure Confirmation of top polymorphisms in hyper-
M; BELHYPGEN Consortium. STK39 and WNK1 are response to a thiazide diuretic. Hypertension. 2005; tension genome wide association study among
potential hypertension susceptibility genes in the 46(4):758–765. Han Chinese. Clin Chim Acta. 2010;411(19–20):
BELHYPGEN Cohort. Medicine (Baltimore). 2016; 261. Catt KJ, Mendelsohn FA, Millan MA, Aguilera G. 1491–1495.
95(15):e2968. The role of angiotensin II receptors in vascular 275. Li J, Shi J, Huang W, Sun J, Wu Y, Duan Q, Luo J,
248. Zhao H, Qi Y, Wang Y, Wang Y, Lu C, Xiao Y, Wang regulation. J Cardiovasc Pharmacol. 1984;6(Suppl 4): Lange LA, Gordon-Larsen P, Zheng SL, Yuan W,
B, Niu W. Interactive contribution of serine/ S575–S586. Wang Y, Popkin BM, Mo Z, Xu J, Du S, Mohlke KL,
threonine kinase 39 gene multiple polymorphisms 262. Higuchi S, Ohtsu H, Suzuki H, Shirai H, Frank GD, Lange EM. Variant mear FGF5 has stronger effects
to hypertension among northeastern Han Chinese. Eguchi S. Angiotensin II signal transduction through on blood pressure in chinese with a higher body
Sci Rep. 2014;4(1):5116. the AT1 receptor: novel insights into mechanisms mass index. Am J Hypertens. 2015;28(8):1031–
249. Umedani LV, Chaudhry B, Mehraj V, Ishaq M. Se- and pathophysiology. Clin Sci (Lond). 2007;112(8): 1037.
rene threonine kinase 39 gene single nucleotide 417–428. 276. Xi B, Shen Y, Reilly KH, Wang X, Mi J. Recapitulation
A-G polymorphism rs35929607 is weakly associated 263. Henderson SO, Haiman CA, Mack W. Multiple of four hypertension susceptibility genes (CSK,
with essential hypertension in population of polymorphisms in the renin- angiotensin-aldosterone CYP17A1, MTHFR, and FGF5) in East Asians.
Tharparkar, Pakistan. J Pak Med Assoc. 2013;63(2): system (ACE, CYP11B2, AGTR1) and their contri- Metabolism. 2013;62(2):196–203.

199–205. bution to hypertension in African Americans and 277. Oldham WM, Hamm HE. Heterotrimeric G protein
250. Fava C, Danese E, Montagnana M, Sjögren M, Latinos in the multiethnic cohort. Am J Med Sci. 2004; activation by G-protein-coupled receptors. Nat Rev
Almgren P, Engström G, Nilsson P, Hedblad B, Guidi 328(5):266–273. Mol Cell Biol. 2008;9(1):60–71.
GC, Minuz P, Melander O. Serine/threonine kinase 264. Chandra S, Narang R, Sreenivas V, Bhatia J, Saluja D, 278. Tesmer JJ. The quest to understand heterotrimeric
39 is a candidate gene for primary hypertension Srivastava K. Association of angiotensin II type 1 G protein signaling. Nat Struct Mol Biol. 2010;17(6):
especially in women: results from two cohort receptor (A1166C) gene polymorphism and its 650–652.
studies in Swedes. J Hypertens. 2011;29(3):484–491. increased expression in essential hypertension: a 279. El Din Hemimi NS, Mansour AA, Abdelsalam MM.
251. Shin DJ, Lee SH, Park S, Jang Y. Association between case-control study. PLoS One. 2014;9(7):e101502. Prediction of the risk for essential hypertension
serine/threonine kinase 39 gene polymorphism, 265. Jinmin L, Jianmin L, Shuqin Z, Xueqiu L, Shuyi T. among carriers of C825T genetic polymorphism of
hypertension, and other cardiovascular risk factors The polymorphism of angiotensin-receptor gene G protein b3 (GNB3) gene. Biomark Insights. 2016;
in Koreans. Korean Circ J. 2013;43(1):13–22. A1166C in familial hypertension and its distribution 11:69–75.
252. Xu J, Ji LD, Zhang LN, Dong CZ, Fei LJ, Hua S, Tsai JY, in the Han Yellow race of China. Saudi Med J. 2013; 280. Nejatizadeh A, Kumar R, Stobdan T, Pasha MQ.
Zhang YP. Lack of association between STK39 and 34(10):1007–1012. Association of GNB3 C825T polymorphism with
hypertension in the Chinese population. J Hum 266. Shahin DS, Irshaid YM, Saleh AA. The A1166C plasma electrolyte balance and susceptibility to
Hypertens. 2013;27(5):294–297. polymorphism of the AT1R gene is associated with hypertension. Genet Mol Biol. 2011;34(4):553–556.
253. Duarte JD, Lobmeyer MT, Wang Z, Chapman AB, an early onset of hypertension and high waist 281. Kumar R, Kohli S, Alam P, Barkotoky R, Gupta M,
Gums JG, Langaee TY, Boerwinkle E, Turner ST, circumference in Jordanian males attending the Tyagi S, Jain SK, Pasha MA. Interactions between the
Johnson JA. Lack of association between poly- Jordan University Hospital. Clin Exp Hypertens. 2014; FTO and GNB3 genes contribute to varied clinical
morphisms in STK39, a putative thiazide response 36(5):333–339. phenotypes in hypertension. PLoS One. 2013;8(5):
gene, and blood pressure response to hydrochlo- 267. Kooffreh ME, Anumudu CI, Duke R, Okpako EC, e63934.
rothiazide. Pharmacogenet Genomics. 2010;20(8): Kumar PL. Angiotensin II type 1 receptor A1166C 282. Kabadou IA, Soualmia H, Jemaa R, Feki M, Kallel A,
516–519. gene polymorphism and essential hypertension in Souheil O, Taieb SH, Sanhaji H, Kaabachi N. G
254. Donner KM, Hiltunen TP, Hannila-Handelberg T, Calabar and Uyo cities, Nigeria. Indian J Hum Genet. protein b3 subunit gene C825T and angiotensin
Suonsyrjä T, Kontula K. STK39 variation predicts the 2013;19(2):213–218. converting enzyme gene insertion/deletion poly-
ambulatory blood pressure response to losartan in 268. Jain S, Prater A, Pandey V, Rana A, Puri N, Kumar A. morphisms in hypertensive Tunisian population.
hypertensive men. Hypertens Res. 2012;35(1): A haplotype of angiotensin receptor type 1 asso- Clin Lab. 2013;59(1–2):85–92.
107–114. ciated with human hypertension increases blood 283. Li M, Zhang B, Li C, Liu JL, Wang LJ, Liu Y, Wang ZG,
255. Xu BE, Lee BH, Min X, Lenertz L, Heise CJ, Stippec S, pressure in transgenic mice. J Biol Chem. 2013; Wen SJ. G-protein beta 3 subunit polymorphisms
Goldsmith EJ, Cobb MH. WNK1: analysis of protein 288(52):37048–37056. and essential hypertension: a case-control associa-
kinase structure, downstream targets, and potential 269. Gong HT, Ma XL, Chen BX, Xu XY, Li Q, Guo CX, Du tion study in northern Han Chinese. J Geriatr
roles in hypertension. Cell Res. 2005;15(1):6–10. FH. Polymorphisms of the angiotensin II type 1 Cardiol. 2015;12(2):127–134.
256. Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa receptor gene affect antihypertensive response to 284. Matayoshi T, Kamide K, Takiuchi S, Yoshii M,
K, Nelson-Williams C, Desitter I, Gunel M, Milford angiotensin receptor blockers in hypertensive Miwa Y, Takami Y, Tanaka C, Banno M, Horio T,
DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Chinese. Genet Mol Res. 2013;12(2):2068–2075. Nakamura S, Nakahama H, Yoshihara F, Inenaga
Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, 270. Kurland L, Hallberg P, Melhus H, Liljedahl U, T, Miyata T, Kawano Y. The thiazide-sensitive
Jeunemaitre X, Lifton RP. Human hypertension Hashemi N, Syvänen AC, Lind L, Kahan T. The Na1-Cl 2 cotransporter gene, C1784T, and ad-
caused by mutations in WNK kinases. Science. 2001; relationship between the plasma concentration of renergic receptor-b3 gene, T727C, may be gene
293(5532):1107–1112. irbesartan and the antihypertensive response is polymorphisms susceptible to the antihyper-
257. Frey MK, Dao F, Olvera N, Konner JA, Dickler MN, disclosed by an angiotensin II type 1 receptor tensive effect of thiazide diuretics. Hypertens Res.
Levine DA. Genetic predisposition to bevacizumab- polymorphism: results from the Swedish Irbesartan 2004;27(11):821–833.
induced hypertension. Gynecol Oncol. 2017;147(3): Left Ventricular Hypertrophy Investigation vs. 285. Whelton PK, Carey RM, Aronow WS, Casey DE Jr,
621–625. Atenolol (SILVHIA) Trial. Am J Hypertens. 2008; Collins KJ, Dennison Himmelfarb C, DePalma SM,
258. Liu F, Lian Q, Ren J, Ren K, Wang Y, Wang D, Chu C, 21(7):836–839. Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ,
Wang L, Guo T, Liu E, Mu J, Yuan Z. Lack of family- 271. Zhan X, Bates B, Hu XG, Goldfarb M. The human Muntner P, Ovbiagele B, Smith SCJ, Spencer CC,
based association between common variations in FGF-5 oncogene encodes a novel protein related to Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr,
WNK1 and blood pressure level. Med Sci Monit. fibroblast growth factors. Mol Cell Biol. 1988;8(8): Williamson JD, Wright JT Jr. 2017 ACC/AHA/AAPA/
2014;20:1958–1962. 3487–3495. ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA
259. Zambrowicz BP, Abuin A, Ramirez-Solis R, Richter LJ, 272. Hanaka H, Hamada T, Ito M, Nakashima H, Tomita guideline for the prevention, detection, evalua-
Piggott J, BeltrandelRio H, Buxton EC, Edwards J, K, Seki S, Kobayashi Y, Imaki J. Fibroblast growth tion, and management of high blood pressure in
Finch RA, Friddle CJ, Gupta A, Hansen G, Hu Y, factor-5 participates in the progression of hepatic adults: a report of the American College of
Huang W, Jaing C, Key BW Jr, Kipp P, Kohlhauff B, fibrosis. Exp Anim. 2014;63(1):85–92. Cardiology/American Heart Association Task Force
Ma ZQ, Markesich D, Payne R, Potter DG, Qian N, 273. Takeuchi F, Isono M, Katsuya T, Yamamoto K, on Clinical Practice Guidelines. Hypertension. 2018;71:
Shaw J, Schrick J, Shi ZZ, Sparks MJ, Van Sligtenhorst Yokota M, Sugiyama T, Nabika T, Fujioka A, Ohnaka 1269–1324.
I, Vogel P, Walke W, Xu N, Zhu Q, Person C, Sands K, Asano H, Yamori Y, Yamaguchi S, Kobayashi S, 286. Chobanian AV, Bakris GL, Black HR, Cushman WC,
AT. Wnk1 kinase deficiency lowers blood pressure Takayanagi R, Ogihara T, Kato N. Blood pressure and Green LA, Izzo JLJ Jr, Jones DW, Materson BJ, Oparil
in mice: a gene-trap screen to identify potential hypertension are associated with 7 loci in the S, Wright JT Jr, Roccella EJ; National Heart, Lung, and

REVIEW
Blood Institute Joint National Committee on Pre- Brigham and Women’s Hospital, Boston, MA, as well as by a AGTR1, angiotensin receptor type I; ANGII, angiotensin II;
vention, Detection, Evaluation, and Treatment of fellowship to W.M. from the Faculty of Medicine, Chiang Mai ATP2B1, plasma membrane calcium-transporting ATPase 1;
High Blood Pressure; National High Blood Pressure University (Chiang Mai, Thailand). AT1R, angiotensin receptor type 1; BDKRB2, bradykinin re-
Education Program Coordinating Committee. The Author Contributions: W.M. and G.H.W. established ceptor B2; CAV1, caveolin-1; cGMP, cyclic GMP; CYP17A1,
seventh report of the Joint National Committee on the survey plan, independently screened the individual cytochrome P450 family 17 subfamily A member 1; CYP11B2,
Prevention, Detection, Evaluation, and Treatment of publications and then, by consensus, identified the publi- cytochrome P450 family 11 subfamily B member 2; EDN1,
High Blood Pressure: the JNC 7 report. JAMA. 2003; cations to be assessed for inclusion/exclusion criteria. W.M. endothelin-1; ENaC, epithelial Na1 channel; eNOS, endo-
289(19):2560–2572. and G.H.W. wrote the manuscript. G.H.W. created the thelial nitric oxide synthase; ER, estrogen receptor; ESR2,
concept of the manuscript and provided the final editing of estrogen receptor b; FGF5, fibroblast growth factor 5; GNB3,
the manuscript. G protein b3 subunit; GWAS, genome-wide association
Correspondence and Reprint Requests: Gordon H. study; LSD1, lysine-specific demethylase 1; MR, mineralo-
Acknowledgments Williams, MD, Brigham and Women’s Hospital, 221 Long-
We thank the students, fellows, and faculty of the Cardio- corticoid receptor; MRA, MR antagonist; NEDD4L, neural
wood Avenue, Boston, Massachusetts 02115. E-mail: gwilliams@ precursor cell expressed developmentally downregulated 4-
vascular Endocrinology Section, Division of Endocrinology,
bwh.harvard.edu.
Diabetes, and Hypertension, Brigham and Women’s Hospital, like; PRA, plasma renin activity; RAAS, renin–angiotensin–
Disclosure Summary: The authors have nothing to
for inspiring and encouraging us to complete this project. We aldosterone system; REN, renin (gene); SGK1, serum- and
disclose.
appreciate the administrative and editorial assistance of Haris glucocorticoid-inducible kinase 1; SLC4A5, electrogenic so-
Lefteri and the artistic assistance of Luminita Pojoga, Chee Sin dium bicarbonate cotransporter 4; SNP, single-nucleotide

Tay, and Jessica Lee. Abbreviations polymorphism; SSBP, salt-sensitive blood pressure; STK39,
Financial Support: This work was supported in part by ACE, angiotensin-converting enzyme; ADD-1, adducin-1; serine/threonine 39; STRN, striatin (gene); WNK1, lysine-
the Division of Endocrinology, Diabetes and Hypertension, ADRb2, b2-adrenergic receptor; AGT, angiotensinogen; deficient protein kinase 1..

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REVIEW

Genetics of Human Primary Hypertension: Focus on

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H ypertension is the leading contributing factor

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deep phenotyping or gene manipulation In each subsection, the genotype/phenotype groups

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Summary of Selected Genotypes/Phenotypes

As stated above, we ﬁrst review the  proximate,

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Table  (, , –, –, , –) for

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