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THE RELATIONSHIP OF SINGLE NUCLEOTIDE POLYMORPHISMS AND

INFLAMMATORY MARKERS OF CORONARY ARTERY DISEASE:
SIGNIFICANCE FOR NURSE PRACTITIONERS IN AN ACUTE CARE SETTING
by
Karl Matthew Stempel

___________________
A Literature Review Submitted to the Faculty of the
COLLEGE OF NURSING
In Partial Fulfillment of the Requirements For the Degree of
MASTER OF SCIENCE AS A FAMILY NURSE PRACTITIONER
In the Graduate College
THE UNIVERSITY OF ARIZONA





2005
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STATEMENT BY AUTHOR
This literature review has been submitted in partial fulfillment of requirements for
a degree at the University of Arizona and is deposited as a PDF file in the College of
Nursing online Thesis, Dissertation, and Project Library to be made available to viewers
under the rules of the Library.
Brief quotations from this literature review are allowable without special
permission, provided that accurate acknowledgement of source is made. Requests for
permission for extended quotation from or reproduction of this manuscript in whole or in
part may be granted by the head of the major department or the Dean of the Graduate
College when in his or her judgment the proposed use of the material is in the interests of
scholarship. In all other instances, however, permission must be obtained from the
author.

SIGNED: _______________________

APPROVAL BY LITERATURE REVIEW DIRECTOR
This literature review has been approved on the date shown below:
__________________________________ ___________________________
Leslie Ritter Date
Professor of Nursing
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ACKNOWLEDGEMENTS
My Lord and Savior, Jesus Christ, without whom I would have never been
admitted to the College of Nursing.
Karl Stempel, College of Nursing, University of Arizona.
Shu-Fen Wung, PhD, College of Nursing, University of Arizona. I would like to
thank Dr. Wung for the assistance and support she provided during the writing of this
literature review. I would not have been able to complete the project without her
continued guidance and critique throughout the writing process.
Correspondence concerning this article should be addressed to Karl Stempel,
College of Nursing, University of Arizona, Tucson, Arizona 85721. E-mail:
karls@u.arizona.edu
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TABLE OF CONTENTS
Statement by Author2
Acknowledgements..3
Table of Contents.4
List of Figures..5
Abstract....6

Chapter I. Introduction
Introduction..7
Etiology of CAD..7

Chapter II. Theoretical Framework and Review of Literature
Theoretical Framework....9
Novel Risk Factors...9
SNPs: the Genetic Link..10
Pathophysiology of Inflammation..12
Literature Review of Single Nucleotide Polymorphisms (SNPs)......15
CR-P Promoting SNPs...16
IL-6 Promoting SNPs....17
Fibrinogen Promoting SNPs..25

Chapter III. Present Study
Summary .......30
Discussion: Implications for Practice & Management......32
Management Strategies..36
Conclusion.....37
References.39
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LIST OF ILLUSTRATIONS AND TABLES

Figure 1, The major inflammatory cytokines10
Figure 2, A very short gene with a C/G polymorphism12
Figure 3, SNPs and the inflammatory response cascade...14
Table 1, Proposed CR-P promoting SNPs.44
Table 2, Proposed IL-6 promoting SNPs...45
Table 3, Proposed fibrinogen promoting SNPs.....46

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ABSTRACT
The purpose of this paper is to elucidate the need for acute care nurse practitioners
(ACNPs) to understand the significance of single-nucleotide polymorphisms (SNPs) and
how they correlate with blood levels of certain inflammatory markers; an increase in
blood levels of these markers may lead to coronary artery disease (CAD) and its
sequelae. Genetic research regarding CAD is comparatively sparse. A comprehensive
review of research articles describing the effects of three primary inflammatory markers
and associated genetic polymorphisms on CAD and coronary sequelae was performed;
findings revealed several key SNPs that have been shown to both increase inflammatory
marker levels and increase clinical coronary-related events. ACNPs need to keep their
practice up-to-date by synthesizing genetics research studying both inflammatory
markers and SNPs. Appropriate management strategies include awareness of
inflammatory marker levels and early pharmacological intervention.
Key Words
Single Nucleotide Polymorphisms, inflammation, C-reactive protein, fibrinogen,
Interleukin-6.
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Chapter I. Introduction
Introduction
CAD is the leading cause of morbidity and mortality in the U.S. Cardiovascular
disease causes over 45% of deaths in the U.S. for men, and over 53% for women
(American Heart Association [AHA], 2005). In 2005, Americans will pay well over
$390 billion in health care costs related to CAD complications. About 70 million
Americans suffer from some form of cardiovascular disease (AHA, 2005).
CAD is an inflammatory process (Plutzky, 2001). The inflammatory process is
mediated by multiple inflammatory blood proteins. These inflammatory proteins, or
markers, are in the plasma; therefore, their levels can be measured. The major
inflammatory markers studied today include C-reactive protein (CR-P), interleukin-6 (IL-
6), and fibrinogen (Pearson et al., 2003). Inflammatory marker levels have been
postulated to be modulated by genetic variations called single-nucleotide polymorphisms
(SNPs).
Etiology of CAD
CAD begins with coronary artery vessel endothelial damage (Cotran, 1999).
CAD is the progressive formation of a fatty plaque that hardens and stiffens arteries,
which may eventually rupture and subsequently form a thrombus. If left unchecked,
CAD eventually leads to myocardial infarction (MI), or death of cardiac tissue. After the
thrombus forms, the coronary artery is either completely or partially occluded. The tissue
supplied by that vessel becomes ischemic, and will die if the thrombus is not dissolved or
removed. When tissue death happens, an MI has occurred (Cotran, 1999). Most MIs
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have been found to occur after a long process of chronic inflammation, in which
moderately stenosed vessels experience plaque rupture and subsequent thrombus
formation (Plutzky, 2001).
Traditional Genetic Risk Factors
Traditional genetically linked risk factors for the development of CAD include
hypertension, dyslipidemia, diabetes, and a family history of CAD (Pearson et al., 2003).
Clearly, genetics plays a crucial role in the manifestation of CAD, yet many heath care
providers consider genetics a field that only applies to specialists (Wung, 2002).
The importance of genetics in CAD was first evidenced with a historic hallmark
study that found first-degree relatives of patients with CAD have a 5-7 fold increased risk
of death due to CAD (Slack & Nevin, 1968). A later study found there is a 4 fold higher
risk of death for fraternal twins and an 8 fold increase in death risk for identical twins that
have a sibling with CAD (Marengberg, Risch, Berkman, Floderus, & de Faire, 1994).
While traditional risk factors certainly are indicative of higher risk of MI, newer
risk factors may be of assistance in determining the urgency of need for acute
intervention, and in verifying the increased risk of MI.
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Chapter II. Theoretical Framework
Novel risk factors
C-reactive protein
C-reactive protein (C-RP) has been called an independent cardiovascular risk
factor (Lagrand et al., 1999). C-RP levels are indicative both of risk for MI and of
outcome after MI (Lagrand, 1999), and there is a dose-response relationship between CR-
P levels and risk of CAD (Pearson et al., 2003). There is also evidence that high C-RP
levels during infections predispose an individual to CAD, and the protein can even be
found localized in inflamed tissues such as infarcted myocardium (Lagrand, 1999).
Indeed, it has been well established that C-RP levels are an independent risk factor for
coronary events (Lagrand et al. [1999], Plutzky [2001], James et al. [2003], and Ichihara
et al. [2002]).
Interleukin-6
Blood levels of C-RP in the acute stages of inflammation can be determined by
levels of IL-6. These two markers have been identified as key markers in the
inflammatory process (Pearson et al., 2003). The IL-6 cytokine stimulates the liver to
release higher levels of CR-P, thus increasing the individuals chance of developing CAD
(Pearson et al. [2003] and Volankis [2001]). High IL-6 levels are also associated with an
increased risk for future coronary events (Saadeddin et al. [2001] and Ridker et al.
[1999]), and even death (Lindmark et al. [2001] and Luc et al. [2003]).
Fibrinogen
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Fibrinogen, another clinical phenotype, also shows promise in determining an
individuals risk for developing MI. An article from the Center for Disease Control
(CDC) and the AHA recently published an exhaustive review article describing
inflammatory markers and their role in cardiovascular disease. This article specifically
state that the strongest association with prognosis has been with fibrinogen(Pearson et
al., 2003). Fibrinogen levels have also been shown to be a good indicator of death rates
in patients with unstable CAD (Lindhal et al. 2000) and of final cardiac infarct size (De
Sutter et al., 2000).
In the respect of correlating CAD with inflammatory blood markers, research and
evidence abounds. The most well-established of these are CR-P, IL-6 and fibrinogen
(Pearson et al., 2003). Research is sparse and inconsistent, however, when it comes to
correlating CR-P, IL-6, and fibrinogen-promoting SNPs with CAD and coronary events.
In theory, genes specific for these phenotypes could be typed in an individual, thereby
determining an individuals level of risk for developing an MI.


IL-6
CR-P
Fibrinogen
Figure 1. The major inflammatory cytokines.
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SNPs: the Genetic Link
Genetic screening for specific polymorphisms is a process in need of further
development. Genetic screening could include genotyping an individual, or analyzing
blood samples for clinical phenotypes (Wung, 2002). Phenotypes are the clinical
manifestation of a genetic variation or mutation. CAD is a complex disease that may
potentially involve hundreds of genetic polymorphisms, called SNPs (See Figure 2). An
SNP (pronounced "snip"), is a small genetic change, or variation, that can occur within a
person's deoxyribonucleic acid (DNA) sequence. The genetic code is specified by the
four nucleotides A (adenine), C (cytosine), T (thymine), and G (guanine). SNP variation
occurs when a single nucleotide, such as an A, replaces one of the other three nucleotide
lettersC, G, or T (NCBI, 2005).
These polymorphisms may predispose an individual to be more susceptible to
plaque formation, high lipid levels, and thrombus formation (Wung, 2002). This review
and critique will attempt to reinforce the mechanism by which the inflammatory process
may beginwith the expression of certain SNPs, which initiate a rise in blood levels of
notorious inflammatory markers such as C-RP, IL-6, and fibrinogen (See Figure 3). This
review will specifically examine one CR-P SNP, six IL-6 SNPs, and five fibrinogen
SNPs in their role in the inflammatory process and in CAD development. These SNPs
were selected because they were the most frequently studied in relationship to CR-P, IL-
6, and the fibrinogen inflammatory markers.
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Pathophysiology of Inflammation
The pathophysiology of CAD is essentially a chronic inflammatory process
(Plutzky [2001], Schonbek & Libby [2004], and Willerson & Ridker [2004]). The
inflammatory process is perhaps the most damaging process in the body for those
susceptible to CAD development (Pearson et al., 2003). Willerson & Ridker (2004)
indicate that the inflammatory process appears to begin with pro-inflammatory risk
factors, such as infectious agents, oxidized low density lipoproteins, or a vascular injury.
The inner lining of the artery, or endothelium, then promotes the migration of leukocytes.
Leukocytes adhere to the endothelium via adhesion molecules, and their presence attracts
more leukocytes and monocytes through the release of additional cytokines (Cotran,
Figure 2. An illustration for a very short gene with a C/G polymorphism.
G A A T C T A G C G A A T C T A G C
G A A T T A G C G A A T T A G C G
G=Guanine
A=Adenine
T=Thymine
C=Cytosine
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1999). The white cells then begin to consolidate into the endothelium, decreasing
endothelial function and increasing matrix degeneration (Schonbeck & Libby, 2004).
The monocytes become macrophages, take up LDLs, and proliferate (Willerson &
Ridker, 2004). The resulting fatty streaks build up over time and increase the lesion size.
A fibrous cap forms over the fatty streak from surrounding vascular smooth muscle cell
production of collagen (Cotran, 1999). This cap is fragile and is eventually dissolved by
the leukocytes through metalloproteinases (Willerson & Ridker, 2004). Throughout the
process, leukocytes and macrophages are releasing proinflammatory modulators, of
which IL-6 is the principal procoagulant cytokine, which in turn increases both CR-P and
fibrinogen levels (Willerson & Ridker, 2004). Fibrinogen and CR-P amplify
inflammatory and coagulopathic responses; CR-P also causes cellular adhesion molecules
to be expressed (Willerson & Ridker, 2004). CR-P is also implicated in directly reducing
nitric oxide (NO) bioavailability. Endothelium-derived NO is a molecule which
enhances vasodilation, inhibits platelet aggregation, reduces leukocyte adherence, and
suppresses smooth muscle cell proliferation (Willerson & Ridker, 2004). As NO levels
gradually decline while inflammatory marker levels increase, the probability of rupture
and thrombosis formation increases (Willerson & Ridker, 2004).
It has been proposed (Jenny et al., [2002], Vickers et al., [2002], Elghannam et al.,
[2000], Basso et al., [2002], Burzotta et al., [2001], Brull et al., [2001], Georges et al.,
[2001], Humphries et al., [2001], Losito et al., [2003], Gaudino et al., [2003], De Maat et
al. [1997], Weng, X., Cloutier, G., & Genest, J. Jr. [1999], Van t Hooft et al. [1999],
Folsom et al. [2001], and Margaglione et al., [2000]) that SNPs are responsible for high
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levels of inflammatory cytokines, and thus exacerbate the inflammatory process through
increasing inflammatory mediators such as IL-6, CR-P, and fibrinogen in the mid to latter
stages of atherosclerosis. While SNPs influencing inflammatory marker levels has yet to
be proven, this paper will attempt to elucidate the significance of single-nucleotide
polymorphisms (SNPs) and how they correlate with blood levels of CR-P, IL-6, and
fibrinogen.
Figure 3. SNPs and the inflammatory response cascade.

Promoter SNPs
Elevated CR-P
Inflammatory and Thrombotic Response
Hypercoagulable blood
WBC
activation
CAD MI
Platelet activation
Endothelial activation
Elevated IL-6 Elevated Fibrinogen
Platelet adhesion and
accumulation
Lipid
deposits/endothelial
remodeling
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Literature Review of Single Nucleotide Polymorphisms
Introduction to Literature Review
The literature search was performed online using Medline. Keywords used were
CAD, MI, and SNP. The most popular SNPs were used for kewords as well. These
SNPs were the C substitution for the G allele at the 174
th
nucleotide in the promoter
region of the IL-6 gene, an A substitution for the G allele at the 455
th
nucleotide in the
promoter region of the beta-fibrinogen gene, and a C substitution for the G allele at the
1059
th
nucleotide in the promoter region of the CR-P gene. There was a much larger
volume of literature found that studied the relationship of SNPs in other inflammatory
conditions such as rheumatoid arthritis (RA), but these were not included because they
were not specific to CAD, MI, or its sequelae.
Articles reviewed had several different ways of describing nucleotide
substitutions and homozygous (two same) or heterozygous (two different) alleles. The
different forms these alleles were described in the body of text of the articles will be the
way they will be described in the literature review. Most described substitutions with a
/ between the normal allele and the substituted allele. For example, if an allele was
normally homozygous with two guanines (GG), a guanine (G) substituted with a cytosine
(C) would be G/C. This was the most popular form of describing the polymorphisms.
Homozygotes are always described without a slash, such as GG. Heterozygotes, such as
the C substitution described above, might also be described with just the C, with the G
allele being implied. All of these nomenclatures follow the locus of the polymorphism;
that is, where the polymorphism appears on the gene. Most popular locations studied are
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described in the previous paragraph as -174 for IL-6, -1059 for CR-P, and -455 for
fibrinogen.
C-RP Promoting SNPs
A C allele substitution for the G allele on the 1059 nucleotide of the CR-P gene
was first discovered by Cao and Hegele in 2000. The study stated the discovery of the
CR-P G1059C polymorphism; no comparisons or experiments were attempted. The
authors proposed that this polymorphism may contribute to high levels of CR-P in
atherosclerotic lesions, leading to MI (Cao & Hegele, 2000). Although this was not a
review article, number of subjects and method of sampling, as well as design of the study,
were not mentioned; as a result, no comments can be made regarding the authors
conclusions.
Zee and Ridker (2002) found that high plasma CR-P levels are associated with the
C allele of the 1059 polymorphism of the CR-P gene, while patients with homozygous
GG allele had lower concentrations. Authors sampled 14, 916 men prospectively over
8.6 years and matched subjects who subsequently developed arterial thrombosis to
controls for a total of 726 case-control pairs. However, there was no significant
association between arterial thrombosis risk and high CR-P levels in all groups (CC, GC,
& GG). The findings of this study indicate a genetic link between high CR-P levels and
the G1059C SNP, but yet appear to contradict a majority of research in showing that high
CR-P levels are not associated with arterial thrombosis risk in this study (Pearson et al.
[2003], Lagrand et al. [1999], Plutzky [2001], James et al. [2003], and Ichihara et al.
[2002]).
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The authors stated, While increased concentrations of C-reactive protein (CRP)
are associated with increased vascular risk, little information is available describing
genetic determinants of this effect (Zee & Ridker, 2002). Therefore, additional research
is warranted.
CR-P Promoting SNP Summary
Cao and Hegele (2000) discovered the CRP G1059C polymorphism; they did not
study its effects on subjects. As a result, no definite conclusions can be drawn from this
study. Zee and Ridker (2002), studying the same polymorphism, discovered that there
were significantly higher levels of CR-P in the C carriers of the CRP G1059C
polymorphism, but were not able to correlate the higher CR-P levels with an increased
risk of arterial thrombosis. It is unclear why this is; it has been well established that
higher CR-P levels correlate with higher risk for MI, which is precipitated by arterial
thrombus formation (Cotran, [1999], Pearson et al., [2003], Lagrand et al., [1999]). See
Table 1 on page 44 for a brief synopsis of proposed CR-P promoting SNP articles
reviewed and their findings.
IL-6 Promoting SNPs
One of the main polymorphisms investigated for IL-6 expression is the C
substitution for the G allele on the 174 nucleotide of the IL-6 gene. The IL-6 G-174C
SNP is implicated in the development of CVD in a cross-sectional, nonexperimental
study conducted by Jenny et al. (2002). The group with a minor C allele had higher
blood levels of CR-P, fibrinogen, and IL-6 when compared to the group with a G allele.
The group with a minor C allele was also at greater risk of developing acute MI. The
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researchers suggested that the minor C allele combined with high IL-6 levels is a
predisposition to atherosclerosis (Jenny et al., 2002). The strengths of this study included
a large sample size of 5201, which included all allele groups and MI/non MI subjects.
Although the findings show a trend toward an increase in IL-6 levels in patients with C
allele than those with G allele, the difference did not show statistical significance.
Vickers and coworkers (2002) found that elevated baseline levels of CR-P are
associated with the IL-6 G174C polymorphism in 588 members of nuclear British
Caucasian families. The authors used a nonexperimental, cross-sectional design. This
article brings forth the argument that acute and chronic CR-P levels brought on by
inflammation may not be the primary impetus for MI development. Carriers of the C
allele of the IL-6 G174C polymorphism may predispose an individual to elevated CR-P
levels and, therefore, acute MI.
In a study by Elghannam et al. (2000), there was an association between baseline
minimum lumen diameter of coronary arteries and the -174G/C genotype in 375 subjects
35-75 years of age with one or more stenotic (30-75%) coronary lesion and high (110-
190 mg/dl) LDL levels randomized to fluvastatin treatment or placebo control groups.
Fluvastatin was found to be effective in reducing lipoprotein (a) in the cohorts with the
CC allele when compared with the GG or GC alleles. The researchers suggested an
association between the GG allele and an increase in high-density lipoprotein (HDL)
levels (p=0.054). Baseline demographic characteristics such as age, gender, ethnic
background, height, weight, body mass index, systolic and diastolic blood pressure,
waist/hip ratio, and history of MI, diabetes, and smoking did not show statistically
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significant relationships with the IL-6 genotypes. Although it is well known that these
characteristics influence a clients risk of MI (Cotran, 1999), the statistically significant
findings in this study of an increased lumen diameter, increased response to fluvastatin,
and decrease in HDL levels with the CC allele show a genetic influence on MI risk
factors. Single polymorphisms may only influence one aspect (i.e., lumen diameter) of a
clients physiologic characteristics; multiple polymorphisms in a population might need
to be studied in order to correlate baseline characteristics with a clients genetic makeup.
Basso et al. (2001) studied the IL-6 -174G/C polymorphism, and a polymorphism
involving a C substitution of the G allele in the 572 locus of the IL-6 gene. A sample of
6595 moderately hypercholesterolemic men ages 45-64 with no prior MI history and no
renal or hepatic dysfunction were randomized to placebo or pravastatin treatment, and
498 cases and 1109 apparently healthy, case-matched controls were selected. The cases
included those experiencing MI, angioplasty, or coronary artery bypass grafting (CABG)
within 4.8 years of follow-up. Participants were genotyped for the above mentioned
polymorphisms, and blood levels of fibrinogen, C-RP, and IL-6 were measured. There
was no significant evidence of higher risk for CAD when the GG, CC, or GC alleles of
the IL-6 -174G/C polymorphism. However, the -174CC genotype had a twofold higher
baseline levels of fibrinogen, CR-P, and IL-6, although the difference did not reach
statistical significance. The -174CC genotype also had the lowest risk of CAD after
pravastatin treatment. Results of this study indicated the individuals with the CC allele
had higher baseline levels of inflammatory markers and the greatest change in CAD risk
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after pravastatin treatment, showing the benefit of research into the IL-6 -174G/C
promoter gene, CAD, and its sequelae.
Higher levels of IL-6 and longer hospital stays were associated with the -174GG
polymorphism of the IL-6 gene in the study conducted by Burzotta et al. (2001). One
hundred eleven patients undergoing elective CABG at one hospital were screened and
then prospectively studied over 16 months using a non-experimental design. Burzotta
found that CABG patients with the GG genotype had higher levels of IL-6 and were in
the ICU longer than C carriers. However, C-RP and fibrinogen level did not differ
significantly among the C carrier and homozygous GG allele groups. Interestingly, the
results from this study differ from results found from previous four studies (Jenny et al.
[2002], Vickers et al. [2002], Elghannam et al. [2000], and Basso et al. [2001]), where the
minor C allele was associated with higher levels of IL-6, fibrinogen, C-RP, and artery
lumen diameter; Burzotta and coworkers found the homozygous GG allele to be
associated with higher levels of IL-6. Although the results show a positive correlation
between the GG allele and IL-6 levels, there was no correlation indicating a relationship
between the GG homozygous allele and the severity of CAD or higher frequency of MI
than the C carriers. This is yet another indication for further research, as both C and GG
alleles have been identified as the culprits for increased IL-6 levels.
Nauck et al. (2002) found no correlation between the -174G/C polymorphism and
IL-6 levels, MI, and CAD in 2559 patients with documented CAD with (n=1365) and
without (n=1194) MI, and 729 non-random controls (no CAD) at a heart center in
Germany. Sampling was done over a 3 year period; the study was called the
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Ludwigshafen Risk and Cardiovascular Health study (LURIC). All CC, GC, and GG
allele subgroups were studied, and none of the groups correlated significantly with IL-6
levels, MI, and CAD. However, IL-6 and CR-P levels were higher in the GC allele.
These findings need to be weighed against other previous study results, since most other
studies reviewed have found a correlation between the IL-6-174C SNP, IL-6 levels, and
acute coronary events (Jenny et al. [2002], Vickers et al. [2002], Elghannam et al. [2000],
and Basso et al. [2001]). Some explanations for the differences in results might include
the possibility that there is more than one SNP that influences IL-6 levels. There is also a
question as to whether the IL-6 -174G/C polymorphism plays more of a role in chronic or
acute IL-6 levels. Additional research needs to be conducted, including IL-6 promoter
polymorphisms at different genetic sites and at different time frames after acute MI
before a conclusion can be reached regarding an association between genotype and
susceptibility to MI and CAD.
After adjusting for age, smoking history, and sex, the -174G/C and -572G/C
polymorphisms of the IL-6 gene were found to be strong predictors of IL-6 levels after
CABG in the study by Brull et al. (2001). One hundred twenty seven patients undergoing
CABG were selected at Middlesex Hospital in England. The study used a
nonexperiemental design, with no control group, intervention, or randomization. The -
597G/A allele was also studied, but no statistically significant results between genotype
and baseline IL-6 levels were found. The -572G/C allele had significantly higher IL-6
levels than the -572GG group 6 hours after surgery. The -174CC group also had higher
IL-6 levels when compared with the -174G carriers. These results support the studies by
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Jenny et al. (2002), Vickers et al. (2002), Elghannam et al. (2000), and Basso et al.
(2001), who found a significant difference between the C allele and IL-6 levels. It may
be beneficial to perform genetic tests on multiple polymorphic sites for each clinical
phenotype; for example, testing the IL-6 -174G/C, -572G/C, and -597G/A SNPs in a
single study; this exemplifies the necessity for continued research in this area.
A study by Georges et al. (2001) found a correlation between the -174G/C, -
572G/C, and -596G/C polymorphisms of the IL-6 gene and susceptibility to MI using a
cross-sectional design. The SNPs were studied to determine effect of genetic variation on
number of stenosed (>50%) coronary vessels. Over a two year period, 640 clients
suffering an acute MI were recruited from health monitoring registers in several
European countries, and 719 age-matched randomly sampled controls. Of note, the -
174G/C and -596G/A polymorphisms were closely associated with one another, having
the highest correlation with three stenosed coronary arteries. The -174C allele was
associated with a higher risk of MI, although this allele was correlated with two or fewer
stenosed vessels, indicating a need to separate the extent of CAD and the susceptibility to
MI as two separate entities. Certain alleles may cause an individual to be more
susceptible to more extensive, yet stable CAD, but not necessarily increase their risk for
MI.
A multivariate analysis showed that the GG genotype of the IL-6 -174G/C
polymorphism was the only independent predictor of postoperative atrial fibrillation
(AF) in a prospective correlational study conducted by Gaudino et al. (2003) in 110
subjects undergoing coronary artery bypass grafting (CABG) at a Catholic hospital in
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Rome. Patients with the GG and the CC genotype were compared. A multivariate
analysis showed that IL-6 and fibrinogen levels were elevated in the GG genotype when
compared to the CC group (p<0.001). In addition, postoperative AF was increased in the
GG allele over the GC and CC alleles (10.4% vs. 33.9%) to within a 95% confidence
interval (CI). This is the only study found that found an increase in IL-6 levels with the
homozygous GG alleles instead of C carriers or the CC homozygote. Most other studies
found the C carriers and the CC homozygote to have increased levels of IL-6 or increased
risk for acute MI (Jenny et al. [2002], Vickers et al. [2002], Elghannam et al. [2000],
Basso et al. [2001], Brull et al. [2001], and Georges et al. [2001]). Brull et al. (2001)
conducted a similar study on postoperative CABG patients and found IL-6 levels to be
elevated in CC alleles as opposed to the GG alleles. Results should therefore be reviewed
with caution; selection methods were not random, no controls were used, and sample size
was small (110). In addition, isolated CABG patients were the only subjects used.
However, these are similar parameters used by Brull et al. (2001). It is otherwise unclear
why Gaudino and colleagues found the GG allele to have higher levels of IL-6,
fibrinogen, and postoperative AF than the -174 CC and C alleles.
Losito et al. (2003) examined 161 dialysis patients with the -174CC and GC allele
of the IL-6 polymorphism in a cross-sectional study, and found that hypertension
(p=0.008) and left ventricular hypertrophy (LVH) were both increased (p=0.026) in both
alleles. Hemodialysis patients in a single unnamed hospital unit were age and gender-
matched to healthy controls. The authors did not study CAD, inflammatory marker
levels and their relationship to the IL-6 -174C allele; they were correlating a risk factor
SNPs and NPs 24
(hypertension) and a result of peripheral vascular disease (LVH) to the allele. The
findings by Losito and colleagues nevertheless shows an association with a majority of
the research by indicating a relationship between the C allele of the -174 polymorphism
and risk factors for acute MI (Jenny et al. [2002], Vickers et al. [2002], Elghannam et al.
[2000], Basso et al. [2001], Brull et al. [2001], and Georges et al. [2001]).
Nakajima et al. (1999) used a case-control design to study 143 normotensive and
150 hypertensive Japanese women recruited from volunteers living in a Japanese
prefecture and found little correlation between hypertension and three new
polymorphisms of the IL-6 gene, the -4391G/A, -634C/G, and -447A/T polymorphisms.
Polymorphisms were similar in frequency in both the normotensive and the hypertensive
groups. No randomization was performed, and no experimental intervention was
involved. The authors concluded that the newly discovered SNPs played a minimal
role, if any, in the genetic etiology of hypertension.
Systolic blood pressure, CR-P, and fibrinogen levels were found to be elevated in
a sample of 2751 healthy, middle-aged U. K. men with the IL-6 -174G/C or CC allele
when compared to the GG allele in a prospective study by Humphries et al. (2001).
There was also no significant effect between blood pressure, fibrinogen, or risk of CAD
and the -572G/C polymorphism. Findings from this study reinforce the majority of other
articles (Jenny et al. [2002], Vickers et al. [2002], Elghannam et al. [2000], Basso et al.
[2001], Brull et al. [2001], Georges et al. [2001, and Losito et al. [2003]) stating the C
allele of the -174G/C polymorphism is the culprit for promoting CAD and its sequelae.
Summary of IL-6 Promoting SNPs
SNPs and NPs 25
The majority of research reported a correlation between the minor C allele at the 174
th

nucleotide of the IL-6 gene and increased IL-6 levels (Jenny et al., [2002], Vickers et al.,
[2002], Elghannam et al., [2000], Basso et al., [2002], Brull et al., [2001], Georges et al.,
[2001], Humphries et al., [2001], and Losito et al., [2003]), except one by Nauck et al.
(2002). Nauck et al. (2002) found none of the CC, GC, or GG alleles of the -174G/C
polymorphism was correlated positively with IL-6 levels, MI, and CAD. It is frankly
unclear as to why this study by Nauck et al. was unable to replicate findings of others. It
is possible that the -174G/C and CC alleles studied do not significantly alter translation
and transcription of proteins and thus affect inflammatory marker levels in some patients.
There may be more than one SNP that influences IL-6 levels, such as the -596GA
polymorphism found by Brull et al. (2001). There needs to be more research conducted
to determine whether the IL-6 -174G/C polymorphism plays more of a role in chronic or
acute IL-6 levels. In short, additional research needs to be conducted with IL-6 promoter
polymorphisms at different genetic sites and at different time frames after acute MI
before a conclusion can be reached regarding an association between the -174G/C
genotype, IL-6 levels, and susceptibility to acute MI. See Table 2 on page 45 for a brief
synopsis of proposed IL-6 promoting SNP articles reviewed and their findings.

Fibrinogen-promoting SNPs
A correlation between CAD and the beta-fibrinogen -455G/A SNP was reported
by de Maat et al. (1998). Using a true double-blind, placebo-controlled experimental
design, authors recruited 885 male clients undergoing catheterization at multiple
SNPs and NPs 26
hospitals. Intervention groups received pravastatin, and controls received placebo. The -
455A/A genotype was especially implicated in significantly higher levels of fibrinogen;
in addition, the 2-year follow up revealed an increased progression of CAD determined
by minimum obstruction diameter (MOD) and mean segment diameter (MSD) for the
placebo group of the same genotype. Pravastatin therapy was given to the treatment
group, and appeared to offset the effect of the A/A genotype in the treatment group after
a 2-year follow-up. The authors propose that clients could be genotyped to determine
who would benefit from early statin treatment, or have other pre-CAD cardioprotective
measures instituted. The study is somewhat old, but employs a strong design to
demonstrate a correlation between CAD and the -455G/A SNP.
Weng, Cloutier, and Genest (1999) discovered an increase in erythrocyte
aggregation related to the beta-fibrinogen -455G/A polymorphism. Study participants
consisted of 135 French Canadians with documented CAD, recruited from a Cardiology
clinic with no controls or intervention. Authors used a cross-sectional, nonexperimental
design. Blood levels were drawn once, 3 months after percutaneous intervention, CABG,
or AMI. Aggregation was measured by laser reflectometry. All three SNP subtypes were
studied; -455GA, -455AA, and -455GG. The -455AA allele had the strongest association
with aggregation, although it was the rarest SNP. The researchers concluded that this
relationship may be explained by a change in the concentration or by the function of the
fibrinogen molecule itself. Since fibrinogen can be associated with the more acute stages
of MI, i.e., thrombosis formation, this study may lend clues into using the beta-fibrinogen
SNPs and NPs 27
-455G/A SNP as more of an acute marker, rather than a chronic, lifetime-developing
CAD marker.
Folsom et al. (2001) studied 398 incident coronary heart disease patients over 5.3
years of follow-ups and compared them to an identical number of participants who were
randomly selected from the same cohort, and found a significantly higher plasma
fibrinogen concentration in those with homozygous AA allele of the -455G/A
polymorphism when compared to the G allele cohort. No association was found between
the A allele carriers and diagnosis of CHD. Although results of this study indicate
minimal correlation of the -455/AA polymorphism to CHD, there is still a correlation of
the -455/AA SNP with increased fibrinogen levels. It is well established that increased
fibrinogen levels correlate with increased CHD risk (Pearson et al., [2003], Lindhal et al.,
[2000], De Sutter et al., [2000]). In addition, all of the studies that find no correlation
between SNP groups used nonexperimental designs; the 2 employing randomized,
interventional, placebo-controlled studies with large cohorts do find statistically
significant differences in SNP groups (Elghannam et al., 2000, and De Maat, 1998).
Margaglione and colleagues (2000) investigated the relationship between several
different serum markers, including fibrinogen, and genetic polymorphisms, such as
fibrinogen G-455A, and a family history of MI in 1048 individuals of variable ethnicity
without clinical evidence of atherosclerosis. They found that the individuals who were
beta-fibrinogen -455A carriers had a trend toward having a first degree relative suffer an
MI than those with GG allele (p=0.08), but found no associations between the allele and
fibrinogen levels. Although fibrinogen levels were raised in individuals who had a first-
SNPs and NPs 28
degree relative suffer an MI, there was no statistical significance found in this study
linking the -455A carriers with fibrinogen levels. Authors conjectured this may be due to
a difference in genetic background from those sampled. Additionally, the results only
reflect the association between a set of variables and a family history of MI (Margaglione
et al. (2000). In other words, authors did not study the risk of MI in subjects recruited.
In a study conducted by Van t Hooft et al. (1999), the 455A and -854A alleles
were associated with higher transcription rates of fibrinogen than their -455G and -854G
counterparts, and together explained approximately 11% of the variation in plasma
fibrinogen concentrations in 210 men randomly recruited from a register of permanent
residents in Stockholm County, Sweden. No control groups were used, and there was no
randomization or experimental intervention in this cross-sectional study. Authors
concluded that the A allele of the -455G/A and -854G/A polymorphisms are
physiologically relevant and have a significant impact on the plasma fibrinogen
concentration. Other common polymorphisms in the beta-fibrinogen gene, -148C/T, -
249C/T, and 993C/T, did not show statistically significant relationship with the
fibrinogen levels. This is the only study investigating any polymorphisms associated
with inflammatory marker levels and CAD and polymorphisms in the fibrinogen gene
other than the -455G/A SNP. Findings from this study support the significance of the -
455A polymorphism to high fibrinogen levels and risk for future MI, which is similar to
results found by others (Maitland, 2002, De Maat, 1997, Weng, 1999, Margaglione,
2000).
Summary of Fibrinogen-promoting SNPs
SNPs and NPs 29
Results from studies examining the beta-fibrinogen-455G/A polymorphism
showed a positive correlation between the SNP and increased serum fibrinogen levels
and/or increased risk for coronary events (De Maat et al., [1998], Weng et al., [1999],
Folsom et al., [2001], Margaglione et al., [2000], Maitland-van der Zee et al., [2002],
Vant Hooft et al., [1999]). The only study examining other polymorphisms was Vant
Hooft (1999), who studied five polymorphisms of the beta-fibrinogen gene, -455G/A, -
854G/A, -148C/T, -249C/T, and -993C/T, and found that only two (-455A and -854A)
increased the plasma fibrinogen concentration. The fact that the other SNPs did not
appear to increase serum fibrinogen levels to a statistically significant degree may
indicate that the substitutions produce no significant effect on translation and subsequent
transcription of the fibrinogen protein. Further research using large sample sizes, a
higher degree of randomization and control, and meta-analysis of all known SNPs
affecting CR-P, IL-6, and fibrinogen levels is warranted to confirm this hypothesis. See
Table 3 on page 46 for a brief synopsis of proposed fibrinogen promoting SNP articles
and their findings.

SNPs and NPs 30
Chapter III. Present Study
Summary
There are very few well-established genetic markers in modern research
implicated in the proliferation of proinflammatory markers, or CAD initiation and
progression (Winkelmann & Hager, 2000). Although CR-P, IL-6 and fibrinogen are
implicated in the inflammatory process leading to CAD and MI, the genetic link has yet
to be established. The genetic literature available correlating SNPs and coronary events
or inflammatory marker levels is not extensive in relation to strictly inflammatory marker
studies, and results from some studies are contradictory. Sample sizes have a high degree
of variation, from hundreds to thousands. Therefore, further research employing
randomized, placebo-controlled, blinded trials with large sample size and studying
multiple SNP markers, such as in the De Maat et al. (1998) study, is warranted to
determine whether there is a high correlation between SNPs, blood levels of
inflammatory markers, and MI incidence.
The most studied polymorphism in the literature currently is the IL-6/-174G/C
polymorphism. Only two studies reported that the -174G allele to be more highly
associated with IL-6 levels (Burzotta et al. [2001], and Gaudino et al. [2003]). The
majority of the articles found the -174C allele has the strongest association with IL-6
levels, CAD, and coronary events (Jenny et al., [2002], Vickers et al., [2002], Elghannam
et al., [2000], Basso et al., [2002], Brull et al., [2001], Georges et al., [2001], Humphries
et al., [2001], and Losito et al., [2003]. Among these studies, only Basso et al. (2002)
and Elghannam et al. (2000) used therapies to improve outcomes; Elghannam et al.
SNPs and NPs 31
(2000) found that fluvastatin decreased mean lumen diameter of coronary arteries in CC
homozygotes, while Basso found pravastatin was the most effective in lowering risk of
CHD in CC homozygotes. In future research, determining which allele is the most
problematic would be most beneficial; this could be accomplished by researching
multiple polymorphisms in relation to CVD. More true experimental designs with
therapies for patients to improve outcomes would also be beneficial.
Besides IL-6 levels, the IL-6 -174C/G SNP is also purported to affect C-RP levels
according to Jenny et al. (2002) and Vickers et al. (2002).
The homozygous and C carriers of the CRP-1059 and IL-6 -572 polymorphisms,
along with the A carrier of the IL-6 -596G/A polymorphism have been implicated in the
increased production of their respective inflammatory markers in several studies (Zee and
Ridker [2002], Brull et al. [2001], Georges et al. [2001], Humprhies et al. [2001]). The
IL-6 -597A SNP, studied only in the Brull et al. article (2001), was not correlated with
high levels of IL-6 after CABG. Three other IL-6 SNPs including -4391A, -634G, and -
447T were examined in only one study by Nakajima et al. (1999), in which authors found
no correlation between these polymorphisms and hypertension. However, theses
polymorphisms are implicated in raised inflammatory marker levels and subsequent
cardiac events require further investigation. Most other studies did not measure
hypertension; they measured serum inflammatory marker levels or risk for acute coronary
events.
Data from five studies showed that the -455AA allele of the beta-fibrinogen gene
is associated with higher fibrinogen levels and subsequent heart-related sequellae than the
SNPs and NPs 32
G allele (De Maat et al. [1997], Weng, X., Cloutier, G., & Genest, J. Jr. [1999], Van t
Hooft et al. [1999], Folsom et al. [2001], Margaglione et al., [2000]). The Margaglione
(2000) study also found marginal statistical significance (p=0.08) between the AA allele
of the beta-fibrinogen -455 gene, when comparing allele frequency of first degree
relatives suffering an MI. This discrepancy, while small, may be a result of the indirect
nature of the measurement; comparing allele frequency with actual subjects who had
suffered an MI, rather than first degree relatives. The evidence is therefore strong that
this allele is associated with higher fibrinogen levels, and therefore heart-related
sequelae.
Several other SNPs of the fibrinogen gene have been proposed to have
implications in the increasing of fibrinogen levels and its possible cardiac effects. The
study by Van t Hooft et al. (1999) found that of the 455A, -854A, -148T, -249T, and
993T SNPs studied, only the -854G/A SNP was positively associated, along with the -
455AA SNP, with a higher rate of fibrinogen production. The -854G/A SNP might be an
important genetic marker for fibrinogen level and thus cardiac consequence.
Discussion: Implications for Practice & Management
Nurse Practitioner Implications: Focus on genetics
So, why should NPs care about genetics? As a professional nurse practitioner, it
is important to know the physiological processes behind the inflammatory process, right
down to the genetic level; this is readily apparent when the results of current reviewed
articles regarding genetics and their correlation with inflammatory blood markers and
coronary sequelae are taken into account. It becomes clear that the savvy NP will rely on
SNPs and NPs 33
more than just family history to determine a clients susceptibility to future coronary
events. Inflammatory marker levels increase during coronary events and decrease
afterward; a clients genetic makeup remains constant (Pearson et al., 2003). Knowing a
clients susceptibility to coronary events through genotyping will improve the clients
plan of care. In the future, ensuring patients are genetically screened for CR-P, IL-6, and
fibrinogen SNPs prior to and as a follow-up to intervention would likely decrease the
clients chances for a future coronary event. Perhaps most important, coronary sequelae
while in the hospital after intervention could be reduced by early pharmacologic
intervention and knowledge of a clients specific genetic predisposition to sequelae. On a
practical level, if a client in the ER is known to be genetically susceptible to coronary
events, early pharmacological interventions that decrease CR-P, fibrinogen, and IL-6
levels could be initiated. CR-P is considered an independent risk factor for MI, and the
probability that CR-P levels are genetically linked cannot be overlooked. Furthermore,
CR-P and other inflammatory marker levels may fluctuate between chronic baseline
levels and acute levels. This could be part of the reason for some of the variability in the
literature reviewed. The genetic link may be helpful when determining a clients
susceptibility for MI.
More genetics research.
Genetics may explain the high blood levels of inflammatory marker
proteins, since proteins are manufactured genetically. Current genetic research displays a
lack of investigating multiple SNPs, with large sample sizes. An experimental design to
increase power of the results would be preferable, although admittedly not always
SNPs and NPs 34
feasible. All but two (Elghannam, [2000], & De Maat, [1998]) of the studies use a
nonexperimental design; control groups are occasionally used. Many are comparative by
nature regardless, so an experimental design would not necessarily be relevant. There is
not enough genetic research involving SNPs, their relationship to inflammatory marker
levels, and coronary sequelae when comparing the volume of research involving
inflammatory marker levels only. Replicated studies testing multiple suspected IL-6,
CR-P, and fibrinogen SNPs need to be tested with experimental designs if possible, and
larger sample sizes.
Genetic markers guiding acute care therapy.
Genotyping an individual for genetic markers specific to IL-6, CR-P, and
fibrinogen before therapy may eventually enable better anticipation of outcomes after
acute care intervention. It could potentially be an excellent indicator of a patients
susceptibility to a certain disease process. Certain individuals may possess SNPs that
promote higher blood levels of inflammatory markers, thus making the host more
susceptible to acute cardiac events. Genotyping can potentially assist nurse practitioners
caring for acutely ill clients in the diagnosis and treatment of specific illnesses, such as
acute coronary syndromes, and custom-tailor treatment based on individual genotype.
For example, a client may have the AA allele of the beta-fibrinogen -455 SNP, and could
be given anti-inflammatory medications before and after acute care intervention, and/or
be placed on chronic treatment to decrease their chance for future coronary events.
Genetic testing specific for IL-6, CR-P, and fibrinogen-promoting SNPs is not ready for
widespread clinical use yet. Although there have been many studies on clinical
SNPs and NPs 35
phenotypes of SNPs, i.e., C-RP and IL-6 levels, only limited studies discussed in this
paper have looked at the genetic makeup of the individuals. Genotypes can potentially
augment existing phenotyping blood tests, as well as encourage lifestyle changes through
helping to explain to an individual that they are especially susceptible to acute coronary
events (Pearson et al., 2003).
Pharmacotherapeutics.
There were only three studies that described treatment based on genotype
susceptibility to high inflammatory marker levels and/or future acute coronary events
(Elghannam et al., [2000], Basso et al., [2002] and De Maat et al., [1997]). These three
studies used pharmacotherapeutics to offset the effects of the offending SNP. Elghannam
(2000) found fluvastatin to be more effective for IL-6-174CC polymorphic cohorts in
reducing lipoprotein (a) in when compared with -174GG or GC alleles. Basso (2001)
indicated that the IL-6-174CC group had higher baseline levels of inflammatory markers
and the greatest change in CAD risk after pravastatin treatment. De Maat (1998) used
pravastatin to decrease fibrinogen levels and decrease risk of a future acute coronary
event. In each study, statins were shown to be beneficial in reducing inflammatory
marker levels and/or risk for acute coronary events. These results indicate
pharmacogenomics might be applied for individualized therapeutics in lowering risk for
MI in genetically susceptible individuals. Therefore, awareness of pharmacogenetic
research can have significant applications for advanced practicing nurses, especially
nurse practitioners who are prescribing medications in individuals with cardiovascular
risks and diseases.
SNPs and NPs 36
Management Strategies
Statins have been shown by multiple studies to lower C-RP levels (Kereiakes,
[2003], Karaca et al., [2003]). However, they also may decrease both IL-6 (Basso et al.,
2002) and fibrinogen levels (De Maat et al., 1998). In fact, a recent review article in the
Circulation journal by Schonbeck and Libby (2004) found that the benefits clients
received from statins were above and beyond what they should have received from lipid-
lowering alone. Authors also indicated that statins reduced proinflammatory serum
marker levels, while enhancing the expression of anti-inflammatory markers, thus
accounting for the additional benefit (Schonbek & Libby, 2004). Inflammatory
mediators such as IL-6 and CR-P levels were reduced by statins and thrombotic
mediators such as fibrinogen were also reduced (Schonbek & Libby, 2004).
ACE inhibitors have been reported in some studies to lower CR-P levels (Uehara,
2003) as well as IL-6 levels (Gage, 2004) and even fibrinogen levels (Fogari et al, [1998],
Gibbs et al, [2001]). ASA plays its own well-known role in reducing platelet aggregation
and reducing inflammation/CRP levels (Kereiakes, 2003). Therefore, a known genetic
predisposition to increased blood levels of CR-P, IL-6 and fibrinogen should prompt the
clinician to begin pharmacotherapy with statins, ASA, and ACE inhibitors.
SNPs and NPs 37
Conclusion
Current literature shows a genetic link between CR-P, IL-6, and fibrinogen levels
and acute coronary events, but the correlation remains to be confirmed. The association
between the CRP 1059C, IL-6-174C and beta-fibrinogen -455A SNPs, inflammatory
markers and acute coronary sequelae should be replicated in future studies. There is
good evidence that the IL-6-174C and beta-fibrinogen -455A SNPs increase
inflammatory marker levels and/or increase risk for acute coronary events (Jenny et al.,
[2002], Vickers et al., [2002], Elghannam et al., [2000], Basso et al., [2002], Brull et al.,
[2001], Georges et al., [2001], Humphries et al., [2001], Losito et al., [2003], and De
Maat et al. [1997], Weng, X., Cloutier, G., & Genest, J. Jr. [1999], Van t Hooft et al.
[1999], Folsom et al. [2001], Margaglione et al., [2000]). The association between other
SNPs such as the CRP-1059C, IL-6-572C, IL-6-596A, and beta-fibrinogen-854A alleles
and an increase in serum CR-P, IL-6, and fibrinogen levels has not been established (Zee
and Ridker [2002], Brull et al. [2001], Georges et al. [2001], Humprhies et al. [2001],
Vant Hooft et al. [1999]). The IL-6/-4391A, -634G, and -447T SNPs show no
correlation with hypertension (Nakajima et al. 1999). The beta-fibrinogen-148T, -249T,
and 993T SNPs show no correlation with inflammatory marker levels or an increased risk
for acute coronary events (Vant Hooft et al. 1999). In the future, genetic testing may
allow more precise treatment through gene-specific drug therapy (Elghannam et al.,
[2000], Basso et al., [2002], and De Maat et al., [1998]). NPs may improve client
outcomes and prevent future coronary events by instituting early pharmacological
SNPs and NPs 38
intervention with ASA, ACE-Is, and statins with clients who are at risk for, or have a
suspected coronary event.
SNPs and NPs 39
References
Basso, F., Lowe, G. D. O., Rumley, A., McMahon, A. D., Humprhies, S. E. (2002).
Arteriosclerosis, Thrombosis, and Vascular Biology. 22, 599-604.

Brull, D. J., Montgomery, H. E., Sanders, J., Dhamrait, L, Luong, L, Rumley, A., et al.
(2001). Interleukin-6 gene -174G>C and -572G>C promoter polymorphisms are
strong predictors of plasma interleukin-6 levels after coronary artery bypass
surgery. Arteriosclerosis, Thrombosis, and Vascular Biology. 21, 1458-1463.

Burzotta, F., Iacoviello, L., Castelnuovo, A. D., Glieca, F., Luciani, N., Zamparelli, R.,
Schiavello, R., Donati, M. B., Maseri, A., Possati, G., Andreotti, F. (2001).
Relation of the -174G/C polymorphism of interleukin-6 to interleukin-6 plasma
levels and to length of hospitalization after surgical coronary revascularization.
American Journal of Cardiology. 88, 1125-1128.

Cao, H., Hegle, R. A. (2000). Human C-reactive protein (CRP) 1059G/C
polymorphism. Journal of Human Genetics. 45, 100-101.

Cotran, R. S., Kumar, V., & Collins, T. (1999). Pathologic basis of disease (6
th
ed.).
Philadelphia, PA: W.B. Saunders Co.

De Maat, M. P. M., Kastelein, J. J. P., Jukema, J. W., Zwinderman, A. H., Jansen, H.,
Groenemeier, Bjorn, et al. (1998). -455G/A polymorphism of the B-fibrinogen
gene is associated with the progression of coronary atherosclerosis in
symptomatic men. Arteriosclerosis, Thrombosis, and Vascular Biology. 18, 265-
271.

Elghannam, H., Tavackoli, S., Ferlic, L., Gotto Jr., A. M., Ballantyne, C. M., Marian, A.
J. (2000). A prospective study of genetic markers of susceptibility to infection
and inflammation, and the severity, progression, and regression of coronary
atherosclerosis and its response to therapy. Journal of Molecular Medicine. 78,
562-568.

Fogari, R., Zoppi, A., Lazzari, P., Preti, P., Mugellini, A., Corradi, L., Lusardi, P. (1998).
ACE inhibition but not angiotensin II antagonism reduces plasma fibrinogen and
insulin resistance in overweight hypertensive patients. Journal of Cardiovascular
Pharmacology. 32(4), 616-620.

Folsom, A. R., Aleksic, N., Ahn , C., Boerwinkle, E., & Wu, K. K. (2001). B-fibrinogen
gene -455G/A polymorphism and coronary heart disease incidence: the
atherosclerosis risk in communities (ARIC) study. Annals of Epidemiology. 11,
166-170.
SNPs and NPs 40
Gage, J. R., Fonarow, G., Hamilton, M., Widawski, M., Martinez-Maza, O., Vredevoe,
D. L. (2004). Beta blocker and angiotensin-converting enzyme inhibitor therapy
is associated with decreased Th1/Th2 cytokine ratios and inflammatory cytokine
production in patients with chronic heart failure. Neuroimmunomodulation.
11(3), 173-180.

Gaudino, M., Andreotti, F., Zamparelli, R., Castelnuovo, A. D., Nasso, G., Burzotta, F.,
Iacoviello, L., Donati, M. B., Schiavello, R., Maseri, A., Possati, G. (2003). The
-174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels
and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory
complication? Circulation. 108(Supp. II), II-195-II-199.

Georges, J., Loukaci, V., Poiier, O., Evans, A., Luc, G., Arveiler, D., et al. (2001).
Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction the
ECTIM study. Journal of Molecular Medicine. 79, 300-305.

Gibbs, C. R., Blann, A. D., Watson, R. D. S., Lip, G. Y. H. (2001). Abnormalities of
hemorheological, endothelial, and platelet function in patients with chronic heart
failure in sinus rhythm. Circulation. 103, 1746-1751.

Heart facts 2003: all Americans. (2003). The American Heart Association. Retrieved
May 8, 2003 from
http://www.americanheart.org/downloadable/heart/1046365800849HFAAFS.pdf

Humphries, S. E., Lunong, L. A., Ogg, M. S., Hawe, E., & Miller, G. J. (2001). The
interleukin-6 -174G/C promoter polymorphism is associated with risk of coronary
heart disease and systolic blood pressure in healthy men. European Heart
Journal. 22, 2243-2252.

Ichihara, Y., Ohno, J., Suzuki, M., Anno, T., Sugino, M., & Nagata, K. (2002). Higher
C-reactive protein concentration and white blood cell count in subjects with more
coronary risk factors and/or lower physical fitness among apparently healthy
Japanese. Circulation Journal. 66, 677-684.

James, S. K., Armstrong, P., Barnathan, E., Califf, R., Lindahl, B., Siegbahn, A., et al.
(2003). Troponin and C-reactive protein have different relations to subsequent
mortality and myocardial infarction after acute coronary syndrome. Journal of
the American College of Cardiology. 41, 916-924.

Jenny, N. S., Tracy, R. P., Ogg, M. S., Luong, L. A., Kuller, L. H., Arnold, A. M.,
Sharrett, A. R., Humphries, S. E. (2002). In the elderly, interleukin-6 plasma
levels and the -174G>C polymorphism are associated with the development of
cardiovascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 22,
2066-2071.
SNPs and NPs 41
Karaka, I., Ilkay, E., Akbulut, M., Yavuzkir, M., Pekdemir, M., Akbulut, H., et al. (2003).
Atrovastatin affects C-reactive protein levels in patients with coronary artery
disease. Current Medical Research and Opinions. 19(3). 187-191.

Kereiakes, D. J. (2003). Adjunctive pharmacotherapy before percutaneous coronary
intervention in non-ST-elevation acute coronary syndromes: the role of
modulation inflammation. Circulation. 108(Suppl. III), 22-27.

Lagrand, W. K., Visser, C. A., Hermens, W. T., Niessen, H. W. M., Verheugt, F. W. A.,
Wolbink, G., et al. (1999). Circulation. 100, 96-102.

Lindhal, B., Toss, H., Siegbahn, A., Venge, P., Wallentin, L. (2000). Markers of
myocardial damage and inflammation in relation to long-term mortality in
unstable coronary artery disease. New England Journal of Medicine. 343, 1139-
1147.

Lindmark, E., Diderholm, E., Wallentin, L., & Siegbahn, A. (2001). Relationship
between interleukin 6 and mortality in patients with unstable coronary artery
disease. Journal of the American Medical Association. 268(17), 2107-2113.

Losito, A., Kalidas, K., Santoni, S., Jefferey, S. (2003). Association of interleukin-6 -
174G/C promoter polymorphism with hypertension and left ventricular
hypertrophy in dialysis patients. Kidney International. 64, 616-622.

Luc, G., Bard, J., Juhan-Vauge, I., Ferrieres, J., Evans, A., Amouyel, P., et al. (2003). C-
reactive protein, interleukin-6, and fibrinogen as predictors of coronary heart
disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 23, 1255-1261.

Marenberg, M. E., Risch, N., Berkman, L. F., et al. (1994). Genetic susceptibility to
death from coronary artery disease in a study of twins. New England Journal of
Medicine, 330(15), 1041-1046.

Margaglione, M., Cappucci, G., Colaizzo, D., Vecchione, G., Grandone, E., Di Minno, G.
(2000). C-reactive protein in offspring is associated with the occurrence of
myocardial infarction in first-degree relatives. Arteriosclerosis, Thrombosis, and
Vascular Biology. 20(1), 198-210.

National Center for Biotechnology Information. (2005). SNPs: Variation on a theme.
Retrieved February 23, 2005, from
http://www.ncbi.nlm.nih.gov/About/primer/snps.html

Nakajima, T., Ota, N., Yoshida, H., Watanabe, S., Suzuki, T., & Emi., M. (1999). Allelic
variants in the interleukin-6 gene and essential hypertension in Japanese women.
Genes and Immunity. 1, 115-119.
SNPs and NPs 42
Nauck, M., Winkelmann, B. R., Hoffman, M., Bohm, B. O., Wienland, H., Marz, W.
(2002). The interleukin-6 G(-174)C promoter polymorphism in the LURIC
cohort: no association with plasma interleukin-6, coronary artery disease, and
myocardial infarction. Journal of Molecular Medicine. 80, 507-513.

Pearson, T. A., Mensah, G. A., Alexander, R. W., Anderson, J. L., Cannon, R. O., Criqui,
M., et al. (2003). Markers of inflammation and cardiovascular disease:
application to clinical and public health practice. Circulation. 107, 499-511.

Plutzky, J. (2001). Inflammatory pathways in atherosclerosis and acute coronary
syndromes. American Journal of Cardiology. 88(Suppl.), 10K-15K.

Ridker, P., Rifai., N., Stampfer, M., Hennekens, C. (2000). Plasma concentration of
interleukin-6 and the risk of future myocardial infarction among apparently
healthy men. Circulation. 101, 1767-1772.

Saaddeddin, S. M., Habbab, M. A., & Ferns, G. A. (2002). Markers of inflammation and
coronary artery disease. Medical Science Monitor. 8(1), RA5-12.

Schonbeck, U., & Libby, P. (2004). Inflammation, immunity, and HMG-CoA Reductase
Inhibitors: Statins as anti-inflammatory agents? Circulation. 109(suppl. II), II-
18-II26.

Slack, J., & Nevin, N. C. (1968). Hyperlipidaemic xanthomatosis. I. Increased risk of
death from ischaemic heart disease in first degree relatives of 53 patients with
essential hyperlipidaemia and xanthomatosis. Journal of Medical Genetics, 5(1),
4-8.

Sutter, J. D., De Buyzere, M., Gheeraert, P., Van de Wiele, C., Voet, J., De Pauw, M., et
al. (2000). Fibrinogen and C-reactive protein on admission as markers of final
infarct size after primary angioplasty for acute myocardial infarction.
Atherosclerosis. 157, 189-196.

Uehara, K., Nomura, M., Ozaki, Y., Fujinaga, H., Ikefuji, H., Kimura, M., Chikamori, K.,
Nakaya, Y., & Ito, S. (2003). High-sensitivity C-reactive protein and left
ventricular remodeling in patients with acute myocardial infarction. Heart
Vessels. 18(2), 67-74.

Van t Hooft, F. M., Von Bahr, S. J. F., Silveira, A., Iliadou, A., Eriksson, P., Hamsten,
A. (1999). Two common, functional polymorphisms in the promoter region of
the B-fibrinogen gene contribute to regulation of plasma fibrinogen concentration.
Arteriosclerosis, Thrombosis, and Vascular Biology. 19, 3063-3070.

SNPs and NPs 43
Vickers, M. A., Green, F. R., Terry, C., Mayosi, B. M., Julier, C., Lathrop, M., Ratcliffe,
P. J., Watkins, H. C., Keavney, B. (2002). Genotype at a promoter
polymorphism of the interleukin-6 gene is associated with baseline levels of
plasma C-reactive protein. Cardiovascular Research. 53, 1029-1034.

Weng, X., Cloutier, G., Genest, J. Jr. (1999). Contribution of the -455G/A
polymorphism at the B-fibrinogen gene to erythrocyte aggregation in patients
with coronary artery disease. Thrombosis and Haemostasis. 82, 1406-1411.

Willerson, J. T., & Ridker, P. M. (2004). Inflammation as a cardiovascular risk factor.
Circulation. 109(suppl. II), II-2-II10.

Winkelmann, B. R., & Hager, J. (2000). Genetic variation in coronary heart disease and
myocardial infarction: methodological overview and clinical evidence.
Pharmacogenomics. 1(1), 73-94.

Wung, S. F. (2002). Genetic advances in coronary artery disease. Paper presented at the
University of Arizona. Tucson, AZ.

Zee, R. Y. L., Ridker, P. M. (2002). Polymorphism in the human C-reactive protein
(CRP) gene, plasma concentrations of CRP, and the risk of future arterial
thrombosis. Atherosclerosis. 162, 217-219.

SNPs and NPs 44
Table 1. Proposed CR-P promoting SNPs.





















Implicated Implicated
Allele Allele
Findings Findings Population Population Author Author
C C Elevated baseline levels of CR Elevated baseline levels of CR- -P assoc. P assoc.
with C substitution at with C substitution at - -174 locus of IL 174 locus of IL- -
6 gene 6 gene
588 members of nuclear British 588 members of nuclear British
Caucasian families Caucasian families
Vickers et al. (2002) Vickers et al. (2002)
C C C substitution of G allele in C substitution of G allele in - -174 region 174 region
of IL of IL- -6 gene higher blood levels of CR 6 gene higher blood levels of CR- -
P, fibrinogen, and IL P, fibrinogen, and IL- -6 than in GG 6 than in GG
5201 adults >65 5201 adults >65 y.o y.o. sampled, those . sampled, those
who developed cardiovascular disease who developed cardiovascular disease
were case were case- -control matched control matched
Jenny et al. (2002) Jenny et al. (2002)
C C C carriers of the CRP 1059 gene had C carriers of the CRP 1059 gene had
higher CR higher CR- -P levels than GG allele P levels than GG allele
14, 916 men prospectively sampled 14, 916 men prospectively sampled
over 8.6 years and matched subjects over 8.6 years and matched subjects
who developed arterial thrombosis to who developed arterial thrombosis to
controls for a total of 726 case controls for a total of 726 case- -control control
pairs pairs
Zee and Zee and Ridker Ridker
(2002) (2002)
C C discovered C substitution for G at the discovered C substitution for G at the
1059 1059
th th
nucleotide in the promoter of the nucleotide in the promoter of the
CR CR- -P gene P gene
(None described) (None described) Cao Cao and and Hegele Hegele
(2000) (2000)
Implicated Implicated
Allele Allele
Findings Findings Population Population Author Author
C C Elevated baseline levels of CR Elevated baseline levels of CR- -P assoc. P assoc.
with C substitution at with C substitution at - -174 locus of IL 174 locus of IL- -
6 gene 6 gene
588 members of nuclear British 588 members of nuclear British
Caucasian families Caucasian families
Vickers et al. (2002) Vickers et al. (2002)
C C C substitution of G allele in C substitution of G allele in - -174 region 174 region
of IL of IL- -6 gene higher blood levels of CR 6 gene higher blood levels of CR- -
P, fibrinogen, and IL P, fibrinogen, and IL- -6 than in GG 6 than in GG
5201 adults >65 5201 adults >65 y.o y.o. sampled, those . sampled, those
who developed cardiovascular disease who developed cardiovascular disease
were case were case- -control matched control matched
Jenny et al. (2002) Jenny et al. (2002)
C C C carriers of the CRP 1059 gene had C carriers of the CRP 1059 gene had
higher CR higher CR- -P levels than GG allele P levels than GG allele
14, 916 men prospectively sampled 14, 916 men prospectively sampled
over 8.6 years and matched subjects over 8.6 years and matched subjects
who developed arterial thrombosis to who developed arterial thrombosis to
controls for a total of 726 case controls for a total of 726 case- -control control
pairs pairs
Zee and Zee and Ridker Ridker
(2002) (2002)
C C discovered C substitution for G at the discovered C substitution for G at the
1059 1059
th th
nucleotide in the promoter of the nucleotide in the promoter of the
CR CR- -P gene P gene
(None described) (None described) Cao Cao and and Hegele Hegele
(2000) (2000)
SNPs and NPs 45
Table 2. Proposed IL-6 promoting SNPs.










































CC CC - -174CC genotype 2x higher (but statistically 174CC genotype 2x higher (but statistically
insignificant) baseline levels of fibrinogen, insignificant) baseline levels of fibrinogen,
CR CR- -P, and IL P, and IL- -6 6
6595 6595 hypercholesterolemic hypercholesterolemic men men
45 45- -64 64 y.o y.o. w/no MI . w/no MI hx hx
randomized to placebo or randomized to placebo or
pravastatin pravastatin treatment treatment
498 cases & 1109 healthy, 498 cases & 1109 healthy,
case case- -matched controls selected matched controls selected
Cases = MI, angioplasty, or Cases = MI, angioplasty, or
CABG within 4.8 years of CABG within 4.8 years of
follow follow- -up up
Basso et al., (2002) Basso et al., (2002)
CC CC Association between baseline minimum lumen Association between baseline minimum lumen
diameter of coronary arteries and diameter of coronary arteries and - -174CC 174CC
genotype genotype
375 subjects 35 375 subjects 35- -75 years of age 75 years of age
with one or more with one or more stenotic stenotic (30 (30- -
75%) coronary lesion and high 75%) coronary lesion and high
(110 (110- -190 mg/dl) LDL levels 190 mg/dl) LDL levels
randomized to randomized to fluvastatin fluvastatin
treatment or placebo control treatment or placebo control
groups groups
Elghannam Elghannam et al. (2000) et al. (2000)
C C Elevated baseline levels of CR Elevated baseline levels of CR- -P assoc. with C P assoc. with C
substitution at substitution at - -174 locus of IL 174 locus of IL- -6 gene 6 gene
588 members of nuclear British 588 members of nuclear British
Caucasian families Caucasian families
Vickers et al. (2002) Vickers et al. (2002)
C C C substitution of G allele in C substitution of G allele in - -174 region of IL 174 region of IL- -
6 gene higher blood levels of CR 6 gene higher blood levels of CR- -P, P,
fibrinogen, and IL fibrinogen, and IL- -6 than in GG 6 than in GG
5201 adults >65 5201 adults >65 y.o y.o. sampled, . sampled,
those who developed those who developed
cardiovascular disease were cardiovascular disease were
case case- -control matched control matched
Jenny et al. (2002) Jenny et al. (2002)
Implicated Implicated
Allele Allele
Findings Findings Population Population Author Author
CC CC - -174CC genotype 2x higher (but statistically 174CC genotype 2x higher (but statistically
insignificant) baseline levels of fibrinogen, insignificant) baseline levels of fibrinogen,
CR CR- -P, and IL P, and IL- -6 6
6595 6595 hypercholesterolemic hypercholesterolemic men men
45 45- -64 64 y.o y.o. w/no MI . w/no MI hx hx
randomized to placebo or randomized to placebo or
pravastatin pravastatin treatment treatment
498 cases & 1109 healthy, 498 cases & 1109 healthy,
case case- -matched controls selected matched controls selected
Cases = MI, angioplasty, or Cases = MI, angioplasty, or
CABG within 4.8 years of CABG within 4.8 years of
follow follow- -up up
Basso et al., (2002) Basso et al., (2002)
CC CC Association between baseline minimum lumen Association between baseline minimum lumen
diameter of coronary arteries and diameter of coronary arteries and - -174CC 174CC
genotype genotype
375 subjects 35 375 subjects 35- -75 years of age 75 years of age
with one or more with one or more stenotic stenotic (30 (30- -
75%) coronary lesion and high 75%) coronary lesion and high
(110 (110- -190 mg/dl) LDL levels 190 mg/dl) LDL levels
randomized to randomized to fluvastatin fluvastatin
treatment or placebo control treatment or placebo control
groups groups
Elghannam Elghannam et al. (2000) et al. (2000)
C C Elevated baseline levels of CR Elevated baseline levels of CR- -P assoc. with C P assoc. with C
substitution at substitution at - -174 locus of IL 174 locus of IL- -6 gene 6 gene
588 members of nuclear British 588 members of nuclear British
Caucasian families Caucasian families
Vickers et al. (2002) Vickers et al. (2002)
C C C substitution of G allele in C substitution of G allele in - -174 region of IL 174 region of IL- -
6 gene higher blood levels of CR 6 gene higher blood levels of CR- -P, P,
fibrinogen, and IL fibrinogen, and IL- -6 than in GG 6 than in GG
5201 adults >65 5201 adults >65 y.o y.o. sampled, . sampled,
those who developed those who developed
cardiovascular disease were cardiovascular disease were
case case- -control matched control matched
Jenny et al. (2002) Jenny et al. (2002)
Implicated Implicated
Allele Allele
Findings Findings Population Population Author Author
C C
CC CC
systolic blood pressure, CR systolic blood pressure, CR- -P, and P, and
fibrinogen levels found elevated in fibrinogen levels found elevated in - -
174GC and CC polymorphisms 174GC and CC polymorphisms
2751 healthy, middle 2751 healthy, middle- -aged U. K. aged U. K.
men men
Humphries et al. Humphries et al.
(2001) (2001)
C C correlation between IL correlation between IL- -6 6 - -174G/C, 174G/C, - -
572G/C, and 572G/C, and - -596G/C polymorphisms and 596G/C polymorphisms and
susceptibility to MI susceptibility to MI
640 clients suffering an acute MI 640 clients suffering an acute MI
were recruited over 2 years from were recruited over 2 years from
health monitoring registers in health monitoring registers in
several European countries; 719 several European countries; 719
age age- -matched randomly sampled matched randomly sampled
controls selected controls selected
Georges et al. Georges et al.
(2001) (2001)
C C - -174G/C and 174G/C and - -572G/C polymorphisms of 572G/C polymorphisms of
the IL the IL- -6 gene found to be strong predictors 6 gene found to be strong predictors
of IL of IL- -6 levels after CABG 6 levels after CABG
127 patients undergoing CABG 127 patients undergoing CABG
were selected at Middlesex Hospital were selected at Middlesex Hospital
in England in England
Brull Brull et al. (2001) et al. (2001)
GG GG Higher levels of IL Higher levels of IL- -6 and longer hospital 6 and longer hospital
stays associated with stays associated with - -174GG 174GG
polymorphism polymorphism
111 patients undergoing elective 111 patients undergoing elective
CABG at one hospital screened and CABG at one hospital screened and
then prospectively studied over 16 then prospectively studied over 16
months months
Burzotta Burzotta et al. et al.
(2001) (2001)
C C
CC CC
systolic blood pressure, CR systolic blood pressure, CR- -P, and P, and
fibrinogen levels found elevated in fibrinogen levels found elevated in - -
174GC and CC polymorphisms 174GC and CC polymorphisms
2751 healthy, middle 2751 healthy, middle- -aged U. K. aged U. K.
men men
Humphries et al. Humphries et al.
(2001) (2001)
C C correlation between IL correlation between IL- -6 6 - -174G/C, 174G/C, - -
572G/C, and 572G/C, and - -596G/C polymorphisms and 596G/C polymorphisms and
susceptibility to MI susceptibility to MI
640 clients suffering an acute MI 640 clients suffering an acute MI
were recruited over 2 years from were recruited over 2 years from
health monitoring registers in health monitoring registers in
several European countries; 719 several European countries; 719
age age- -matched randomly sampled matched randomly sampled
controls selected controls selected
Georges et al. Georges et al.
(2001) (2001)
C C - -174G/C and 174G/C and - -572G/C polymorphisms of 572G/C polymorphisms of
the IL the IL- -6 gene found to be strong predictors 6 gene found to be strong predictors
of IL of IL- -6 levels after CABG 6 levels after CABG
127 patients undergoing CABG 127 patients undergoing CABG
were selected at Middlesex Hospital were selected at Middlesex Hospital
in England in England
Brull Brull et al. (2001) et al. (2001)
GG GG Higher levels of IL Higher levels of IL- -6 and longer hospital 6 and longer hospital
stays associated with stays associated with - -174GG 174GG
polymorphism polymorphism
111 patients undergoing elective 111 patients undergoing elective
CABG at one hospital screened and CABG at one hospital screened and
then prospectively studied over 16 then prospectively studied over 16
months months
Burzotta Burzotta et al. et al.
(2001) (2001)
SNPs and NPs 46
Table 2. Proposed IL-6 promoting SNPs (continued).




















Table 3. Proposed fibrinogen promoting SNPs.


Implicated Allele Implicated Allele Findings Findings Population Population Author Author
___ ___ no correlation between hypertension no correlation between hypertension
and IL and IL- -6 6 - -4391G/A, 4391G/A, - -634C/G, and 634C/G, and - -
447A/T polymorphisms 447A/T polymorphisms
143 143 normotensive normotensive and 150 and 150
hypertensive Japanese women hypertensive Japanese women
recruited from volunteers living in recruited from volunteers living in
a Japanese prefecture a Japanese prefecture
Nakajima et al. Nakajima et al.
(1999) (1999)
___ ___ no correlation between the no correlation between the - -174G/C 174G/C
polymorphism and IL polymorphism and IL- -6 levels, MI, 6 levels, MI,
and CAD and CAD
2559 patients with documented 2559 patients with documented
CAD with (n=1365) and without CAD with (n=1365) and without
(n=1194) MI, and 729 non (n=1194) MI, and 729 non- -random random
controls (no CAD) at a heart center controls (no CAD) at a heart center
in Germany in Germany
Nauck Nauck et al. (2002) et al. (2002)
GG GG - -174GG genotype w/increased post 174GG genotype w/increased post- -op op
(CABG) AF and IL (CABG) AF and IL- -6 levels 6 levels
110 subjects undergoing CABG at 110 subjects undergoing CABG at
a Catholic hospital in Rome a Catholic hospital in Rome
Gaudino Gaudino et al. (2003) et al. (2003)
C C
CC CC
- -174CC and GC allele both 174CC and GC allele both
w/increased hypertension and LVH w/increased hypertension and LVH
when compared to GG allele when compared to GG allele
161 dialysis patients 161 dialysis patients Losito Losito et al. (2003) et al. (2003)
Implicated Allele Implicated Allele Findings Findings Population Population Author Author
___ ___ no correlation between hypertension no correlation between hypertension
and IL and IL- -6 6 - -4391G/A, 4391G/A, - -634C/G, and 634C/G, and - -
447A/T polymorphisms 447A/T polymorphisms
143 143 normotensive normotensive and 150 and 150
hypertensive Japanese women hypertensive Japanese women
recruited from volunteers living in recruited from volunteers living in
a Japanese prefecture a Japanese prefecture
Nakajima et al. Nakajima et al.
(1999) (1999)
___ ___ no correlation between the no correlation between the - -174G/C 174G/C
polymorphism and IL polymorphism and IL- -6 levels, MI, 6 levels, MI,
and CAD and CAD
2559 patients with documented 2559 patients with documented
CAD with (n=1365) and without CAD with (n=1365) and without
(n=1194) MI, and 729 non (n=1194) MI, and 729 non- -random random
controls (no CAD) at a heart center controls (no CAD) at a heart center
in Germany in Germany
Nauck Nauck et al. (2002) et al. (2002)
GG GG - -174GG genotype w/increased post 174GG genotype w/increased post- -op op
(CABG) AF and IL (CABG) AF and IL- -6 levels 6 levels
110 subjects undergoing CABG at 110 subjects undergoing CABG at
a Catholic hospital in Rome a Catholic hospital in Rome
Gaudino Gaudino et al. (2003) et al. (2003)
C C
CC CC
- -174CC and GC allele both 174CC and GC allele both
w/increased hypertension and LVH w/increased hypertension and LVH
when compared to GG allele when compared to GG allele
161 dialysis patients 161 dialysis patients Losito Losito et al. (2003) et al. (2003)
Implicated Allele Implicated Allele Findings Findings Population Population Author Author
A A beta beta- -fibrinogen fibrinogen - -455A carriers trend 455A carriers trend
toward having a first degree relative toward having a first degree relative
suffer MI than those with GG allele suffer MI than those with GG allele
1048 individuals of variable 1048 individuals of variable
ethnicity without clinical evidence of ethnicity without clinical evidence of
atherosclerosis atherosclerosis
Margaglione Margaglione et al. et al.
(2000) (2000)
AA AA higher plasma fibrinogen concentration higher plasma fibrinogen concentration
with homozygous AA allele of with homozygous AA allele of - -455G/A 455G/A
polymorphism polymorphism
398 CAD patients over 5.3 years of 398 CAD patients over 5.3 years of
follow follow- -ups compared to identical ups compared to identical
number of participants randomly number of participants randomly
selected from the same cohort selected from the same cohort
Folsom et al. (2001) Folsom et al. (2001)
A A 455A and 455A and - -854A alleles associated 854A alleles associated
with higher transcription rates of with higher transcription rates of
fibrinogen than fibrinogen than - -455G and 455G and - -854G 854G
counterparts counterparts
210 men randomly recruited from a 210 men randomly recruited from a
register of permanent residents in register of permanent residents in
Stockholm County, Sweden Stockholm County, Sweden
Van t Van t Hooft Hooft et al. et al.
(1999) (1999)
A A increase in erythrocyte aggregation with increase in erythrocyte aggregation with
beta beta- -fibrinogen fibrinogen - -455G/A polymorphism 455G/A polymorphism
135 French Canadians with 135 French Canadians with
documented CAD, recruited from a documented CAD, recruited from a
Cardiology clinic Cardiology clinic
Weng Weng, X., , X., Cloutier Cloutier, ,
G., & G., & Genest Genest, J. Jr. , J. Jr.
(1999) (1999)
AA AA - -455A/A genotype implicated in higher 455A/A genotype implicated in higher
levels of fibrinogen and progression of levels of fibrinogen and progression of
CAD CAD
Pravastatin Pravastatin therapy given to treatment therapy given to treatment
group offset the effect of the A/A group offset the effect of the A/A
genotype genotype
885 male clients undergoing 885 male clients undergoing
catheterization at multiple hospitals catheterization at multiple hospitals
De De Maat Maat et al. et al.
(1997) (1997)
Implicated Allele Implicated Allele Findings Findings Population Population Author Author
A A beta beta- -fibrinogen fibrinogen - -455A carriers trend 455A carriers trend
toward having a first degree relative toward having a first degree relative
suffer MI than those with GG allele suffer MI than those with GG allele
1048 individuals of variable 1048 individuals of variable
ethnicity without clinical evidence of ethnicity without clinical evidence of
atherosclerosis atherosclerosis
Margaglione Margaglione et al. et al.
(2000) (2000)
AA AA higher plasma fibrinogen concentration higher plasma fibrinogen concentration
with homozygous AA allele of with homozygous AA allele of - -455G/A 455G/A
polymorphism polymorphism
398 CAD patients over 5.3 years of 398 CAD patients over 5.3 years of
follow follow- -ups compared to identical ups compared to identical
number of participants randomly number of participants randomly
selected from the same cohort selected from the same cohort
Folsom et al. (2001) Folsom et al. (2001)
A A 455A and 455A and - -854A alleles associated 854A alleles associated
with higher transcription rates of with higher transcription rates of
fibrinogen than fibrinogen than - -455G and 455G and - -854G 854G
counterparts counterparts
210 men randomly recruited from a 210 men randomly recruited from a
register of permanent residents in register of permanent residents in
Stockholm County, Sweden Stockholm County, Sweden
Van t Van t Hooft Hooft et al. et al.
(1999) (1999)
A A increase in erythrocyte aggregation with increase in erythrocyte aggregation with
beta beta- -fibrinogen fibrinogen - -455G/A polymorphism 455G/A polymorphism
135 French Canadians with 135 French Canadians with
documented CAD, recruited from a documented CAD, recruited from a
Cardiology clinic Cardiology clinic
Weng Weng, X., , X., Cloutier Cloutier, ,
G., & G., & Genest Genest, J. Jr. , J. Jr.
(1999) (1999)
AA AA - -455A/A genotype implicated in higher 455A/A genotype implicated in higher
levels of fibrinogen and progression of levels of fibrinogen and progression of
CAD CAD
Pravastatin Pravastatin therapy given to treatment therapy given to treatment
group offset the effect of the A/A group offset the effect of the A/A
genotype genotype
885 male clients undergoing 885 male clients undergoing
catheterization at multiple hospitals catheterization at multiple hospitals
De De Maat Maat et al. et al.
(1997) (1997)