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Received: 18 October 2017    Revised: 5 December 2017    Accepted: 20 December 2017

DOI: 10.1111/jch.13225

O R I G I N A L PA P E R

Genetic factors contributing to hypertension in African-­based

populations: A systematic review and meta-­analysis

Yandiswa Y. Yako PhD1 | Eric V. Balti MD, PhD2 | Tandi E. Matsha PhD3 | 

Anastase Dzudie MD, PhD4 | Deirdre Kruger PhD5 | Eugene Sobngwi MD, PhD6 | 
Charles Agyemang PhD7 | Andre P. Kengne MD, PhD8

1
Department of Human Biology, Faculty of
Health Sciences, Walter Sisulu University, In a systematic review, the authors explored genetic association studies of essential
Mthatha, South Africa hypertension in African populations. Studies reporting on the association of
2
Diabetes Research Center and Diabetes polymorphism(s) with hypertension in African populations were included. Appropriate
Clinic, Department of Internal Medicine, Free
University of Brussels, Brussels, Belgium studies were pooled using random effects model meta-­analysis, under six potential
3
Department of Biomedical Sciences, Faculty inheritance models. In all, 46 polymorphisms in 33 genes were investigated for their
of Health and Wellness Science, Cape
association with hypertension or blood pressure levels. Meta-­analysis was possible for
Peninsula University of Technology, Cape
Town, South Africa three single nucleotide polymorphisms: rs4340, rs699, and rs5186. An association was
4
Faculty of Medicine and Biomedical Sciences, found between rs5186, rs699, and hypertension under allele contrast and homozy-
University of Yaounde 1, Yaounde, Cameroon
5
gous codominant models (odds ratio, 1.63 [95% confidence interval, 1.04–2.54] and
Department of Surgery, Faculty of Health
Sciences, University of Witwatersrand, 4.01 [95% confidence interval, 1.17–13.80] for rs5186, respectively; and 1.80 [95%
Johannesburg, South Africa confidence interval, 1.13–2.87] for rs699). Findings were mostly robust in sensitivity
6
Department of Internal Medicine and
analyses. According to the systematic review, there is currently insufficient evidence
Specialities, Faculty of Medicine and
Biomedical Sciences, University of Yaounde 1, on the specific polymorphisms that pose the risk of hypertension in African popula-
Yaounde, Cameroon
tions. Large-­scale genetic studies are warranted to better understand susceptibility
7
Department of Public Health, Academic
Medical Center, University of Amsterdam,
polymorphisms that may be specific to African populations.
Amsterdam, The Netherlands
8
Non-Communicable Diseases Research
Unit, South African Medical Research Council,
Cape Town, South Africa

Correspondence
Prof Andre Pascal Kengne, MD, PhD, Non-
Communicable Diseases Research Unit, South
African Medical Research Council, Cape Town,
South Africa.
Email: Andre.kengne@mrc.ac.za;
apkengne@yahoo.com

Funding information
South African Medical Research Council.

1 |  BACKGROUND
Hypertension was rarely reported in the early 20th century but is now
recognized as the leading cardiovascular risk factor in African popu-
1,2
lations. Africa has the highest prevalence of hypertension, particu-
larly among persons 25 years and older, predominantly in sub-­Saharan
Africa.1,3 The increasing prevalence rate of hypertension has been
particularly evident in this region, from approximately 80 million in
2000 to projections of 150 million by 2025.4 The burden associated
with hypertension relates to cardiovascular5 and renal complications,
which have also increased in African populations. The growing hyper-
tension and related complications are attributed to environmental

J Clin Hypertens. 2018;00:1–11. ©2018 Wiley Periodicals, Inc. |  1

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2       YAKO et al.
and behavioral changes including exposure to air pollution, increased
alcohol consumption, tobacco use, sedentary lifestyle, adoption of a
high-­salt diet,6 and consumption of refined sugar and unhealthy fats
and oils.
Apart from environmental and lifestyle factors, genetics also play
a major role in facilitating hypertension occurrence. According to fam-
ily and twin studies, the heritability of hypertension ranges from 24%
to 50%.7,8 Hypertension exists not only as a monogenic trait but also
as the essential type, which accounts for 95% of all cases of hyperten-
9
sion. While monogenic hypertension is well defined with 12 caus-
ative genes, essential hypertension involves a complex interaction
of multiple polymorphisms in numerous genes. More than 60 single
nucleotide polymorphisms (SNPs) have been reported in European
10,11 12 13,14
populations, African Americans, and Asians. According to
these studies, known loci account for only 2.5% of the phenotypic
variance for systolic and diastolic blood pressure (BP). It is speculated
that the missing heritability may be elucidated through search for rare
and structural sequence variants, epigenetics, and investigating gene-­
environment interactions.15 While modifiable risk
gene and gene-­
factors for hypertension are well established in African countries, the
contribution of genetic factors remains elusive. The current system-
atic review focused on collating genetic association studies of hyper-
tension conducted in African populations residing in their respective
countries and critically assessing the extent to which these studies
were performed.
2 |  METHODS
2.1 | Data source and selection of studies
We conducted a systematic review of genetic association studies
performed in populations residing in African countries, following
the Systematic Reviews of Genetic Association Studies protocol. 16
Four databases (PubMed, Embase, Scopus, and Web of Science)
were searched using a combination of terms illustrated in Tables
S1 and S2. This was supplemented by searching reference lists for
relevant articles. Two investigators independently conducted the
literature search to identify all potential studies related to poly-
morphisms associated with essential hypertension in populations
residing in African countries. The last search date was July 21,
2017.
2.2 | Selection criteria
Studies were included if they met the following criteria: (1) inves-
tigated the association between polymorphisms and essential hy-
pertension in Africa-­
based populations, (2) were original studies
containing independent data, (3) were a case-­
control or cohort
design, and (4) contained sufficient data to calculate the odd ratio
(OR) with a confidence interval (CI). Studies were excluded if they:
(1) were duplicate publications, (2) reported selectively on migrant
Africans outside Africa, (3) were family studies, (4) used linkage
analysis, (5) were secondary hypertension studies, and (6) analyzed
mixed populations of African descent without considering their
country of residence.
2.3 | Data extraction
Two reviewers independently extracted the following data from
selected studies: first author and year of publication, study set-
ting and design, population characteristics (number of cases and
controls, and distribution of various genotypes), genetic models,
Hardy-­Weinberg equilibrium (HWE) test, and measures of genetic
association and adjustment for confounders. Disagreements were
resolved by consensus. The presence of bias was assessed by con-
sidering the following: case definition, population stratification,
and reporting of methods used (sample size, genotyping method
and its reliability/accuracy, validation of results, and statistical
analyses).
2.4 | Statistical analyses
For polymorphisms assessed by more than two studies, we used
random effects model meta-­analysis to derive the pooled OR and
95% CIs for the association with prevalent hypertension under six
types of inheritance models: contrast, homozygote codominant,
heterozygote codominant, dominant, overdominant, and reces-
sive models. The departure from HWE of each study was retested,
and credibility of the pooled association was assessed using the
Venice interim criteria.17 Heterogeneity across studies was as-
sessed using the Q-­statistic and quantified using the I2 statistics.18
The Egger test was used to diagnose publication bias.19 Potential
outliers were investigated in sensitivity analysis by dropping each
study at a time. The Duval and Tweedie trim-­and-­fill method was
used to adjust estimates for the effects of publication bias. Data
analysis used R version 3.3.3 (2017-­03-­06; The R Foundation for
Statistical Computing) and meta-­package. This systematic review is
reported according to the recommendation of the HuGE Handbook
and Preferred Reporting Items for Systematic Reviews and Meta-­
Analyses statement (checklist available in Table S3).
3 | RESULTS
3.1 | Literature search
Figure 1 summarizes the studies selection process. We retrieved
409 records through searches: PubMed (n = 164), Embase (n = 136),
Web of Science (n = 127), Scopus (n = 5), and reference lists (n = 1).
After removing duplicates and screening titles and abstracts, the full
text of 53 publications was assessed for eligibility. Of these, 15 were
excluded for the following reasons: the study population was com-
prised of family members (n = 5), missing data (n = 1), different study
design (eg, investigated the effect of polymorphisms in the plasma
renin-­angiotensin-­aldosterone system in patients with hypertension,
assessed the combined effect of multiple genes on hypertension,
ecological variability and its relationship with fives genes involved in
YAKO et al.       3|

Pubmed Embase Scopus Web of Science

(n = 164) (n = 136) (n = 5) (n = 127)

Duplicates (n = 59)

Reference lists of relevant articles Records screened

(n = 1) (n = 373)
Records excluded:
• Irrelevant titles and abstracts (n = 210)
• Conference proceedings, comments,
editorials (n = 14)
• Reviews (n = 58)
• Studies in non-African countries (n = 41)

Full-text articles screened

(n = 53)
Excluded full-text articles:
Family-based studies (n = 5)
Missing data (n = 1)
Different study design (n = 3)
Combined heterozygous and minor
homozygous genotypes reported (n = 2)
African populations combined with
African Americans (n = 1)
Not accessible (n = 3)
Selected studies
F I G U R E   1   Flowchart for the studies (n = 38)
selection process

regulation of BP) (n = 3), the frequency of the heterozygous and minor

homozygous genotypes were reported as a combined number (n = 2),
African populations were analyzed together with African Americans
(n = 1), and three articles were not accessible. Finally, 38 studies were
included in this review.
3.2 | Characteristics of studies
Study characteristics are presented in Table S4. The majority
(n = 34, 92%) used a case-­control design. Nine studies were con-
ducted in Tunisia; eight in South Africa; six in Egypt; five in Ghana;
three in Algeria; and two in Cameroon, Nigeria, and Morocco each;
and one in Burkina Faso. Twenty studies (53%) did not report on
the ethnicity of the study population. Studies varied according to
the number of included participants, which ranged from 65 to 1939.
Most studies defined hypertension as systolic BP/diastolic BP
(SBP/DBP) ≥140/90 mm Hg or the use of antihypertensive medi-
cations at inclusion. Other studies used either auscultatory DBP
>90 mm Hg or 24-­hour ambulatory DBP >85 mm Hg20 and aus-
21 22
cultatory DBP >95 mm Hg, SBP/DBP >139/89 mm Hg, SBP/
DBP >140/90 mm Hg,2324 SBP/DBP ≥125/80 mm Hg,25 seated DBP
>60 mm Hg, 26
and SBP/DBP >159/94 mm Hg. 27
Ranjith and col-
28
leages did not assign any values to define hypertensive status. On
the other hand, Kooffreh and coworkers 29
grouped patients with
hypertension according to the severity of the disease as prehyper-
tension (SBP/DBP: 120–139/80–89 mm Hg), stage 1 hypertension
(SBP/DBP: 140–159/90–99 mm Hg), and stage 2 hypertension
(SBP/DBP ≥160/100 mm Hg). AbdRaboh and colleagues 30
included
patients who had stage 1 hypertension (SBP/DBP > 140–145/90–
95 mm Hg) or were using at least one antihypertensive medication.
3.3 | Genetic assessment and associations
A total of 46 polymorphisms in 33 genes were investigated for their as-
sociation with prevalent hypertension and/or BP. None of the studies
conducted a genome-­wide scan; instead a candidate gene approach
was used. The polymerase chain reaction–restriction fragment length
polymorphism was a genotyping method of choice for most studies
(55.3%). Five studies22,28,30–32 did not provide covariates adjustment,
while six22,27,33–37 reported P values without effect estimates (Table
S5). Some investigators included multiethnic populations, but partici-
pants were stratified by tribes or chiefdoms in only one study.38
The widely studied polymorphisms were those in genes of the
renin-­angiotensin-­aldosterone system (RAAS) including angiotensin-­
converting enzyme (ACE) I/D (n = 9 studies), angiotensinogen (AGT)
M235T (n = 7), and angiotensin II type 1 receptor (AGTR1) 1166A>C
(n = 7). The SNPs of these genes were included in the meta-­analysis.
Four of the 30 polymorphisms (CPS1-­T1405N; BSND-­43V>I; SH2B3-­
W262R; GNB3-­825C>T; AGT-­
T174M) that were investigated by
one to three studies deviated from HWE. We also observed variable
associations of the 30 SNPs in relation to hypertension or its traits
(Table S5). For example, AGT-­T147M was investigated in Algerian39
and Ghanaian33 populations, and demonstrated association with both
SBP and DBP only in Ghanaians. On the other hand, MTFHR-677C>T
was studied in Algerians40 and Cameroonians37 with no evidence of
association in both populations, while in Moroccans an increased risk
of hypertension was found in TT carriers.41 One polymorphism (NPCR-­
55C>A) had low minor allele frequency and could not be assessed for
its role in hypertension.24 Seventeen of the remaining 27 polymor-
phisms demonstrated statistically significant associations with hyper-
tension, SBP, or DBP (Table S5).
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4       YAKO et al.

Reference (ATR1) Country Odds Ratio Odd ratio 95% CI Weight (%)
Williams et al. 2004 Ghana 1.00 [0.19; 5.27] 5.9
Farrag et al. 2011 Egypt 1.13 [0.11; 11.30] 3.3
Ghogomu et al. 2016 Cameroon 1.24 [0.81; 1.89] 24.9
Mehri et al. 2012 Tunisia 2.92 [2.12; 4.02] 27.5
Ranjith et al. 2004 South African 2.06 [0.94; 4.54] 16.0
Tchelougou et al. 2015 Burkina Faso 1.01 [0.35; 2.91] 11.4
Kooffreh et al. 2013 Nigeria 1.17 [0.39; 3.48] 10.9
Random effects model [1.04; 2.54] 100.0
1.63
Heterogeneity: I2= 56%, r2= 0.1604, p = 0.03
Egger Test p-value = 0.2372 0.5 1 2 10
Odds Ratio & 95% Confidence intervals (Allele contrast model)

Reference Country Odds Ratio Odd ratio 95% CI Weight (%)

Williams et al. 2004 Ghana 0.80 [0.14; 4.50] 10.6

Farrag et al. 2011 Egypt 0.10 [0.01; 1.08] 7.2
Ghogomu et al. 2016 Cameroon 1.44 [0.26; 8.08] 10.6
Mehri et al. 2012 Tunisia 4.65 [2.59; 8.34] 21.1
Ranjith et al. 2004 South African 1.91 [0.80; 4.55] 18.3
Tchelougou et al. 2015 Burkina Faso 1.01 [0.35; 2.93] 16.3
Kooffreh et al. 2013 Nigeria 1.17 [0.39; 3.50] 16.0

1.38 [0.65; 2.92] 100.0

Random effects model
Heterogeneity: I2= 66%, r2= 0.6083, p = 0.02 0.01 0.1 1 10 100
Egger Test p-value = 0.005148 Odds Ratio & 95% Confidence intervals (Dominant model)

Reference Country Odds Ratio Odd ratio 95% CI Weight (%)

Williams et al. 2004 Ghana 1.22 [0.05; 30.56] 11.3
Farrag et al. 2011 Egypt 0.0
Ghogomu et al. 2016 Cameroon 0.61 [0.20; 1.84] 33.1
Mehri et al. 2012 Tunisia 3.45 [2.11; 5.66] 41.7
Ranjith et al. 2004 South African 11.02 [0.68; 179.52] 13.9
Tchelougou et al. 2015 Burkina Faso 0.0
Kooffreh et al. 2013 Nigeria 0.0
Random effects model
2.03 [0.58; 7.13] 100.0
Heterogeneity: I2= 67%, r2= 9183, p = 0.03
Egger Test p-value = 0.938 0.01 0.1 1 10 100
Odds Ratio & 95% Confidence intervals (Recessive model)

Reference Country
Odds Ratio Odd ratio 95% CI Weight (%)
Williams et al. 2004 Ghana [0.10; 3.66] 3.1
Egypt 0.59 1.9
Farrag et al. 2011 [0.01; 1.08]
Cameroon 0.10 11.4
Ghogomu et al. 2016 [0.62; 4.18]
Tunisia 1.61 53.8
Mehri et al. 2012 [0.68; 1.64]
South African 1.06 12.2
Ranjith et al. 2004 [0.65; 4.10]
Burkina Faso 1.63 9.1
Tchelougou et al. 2015 [0.35; 2.93]
Nigeria 1.01 8.6
Kooffreh et al. 2013 [0.39; 3.50]
1.17
1.11 [0.80; 1.53] 100.0
Random effects model
Heterogeneity: I2= 0%, r2= 0, p = 0.45 0.01 0.1 1 10 100
Egger Test p-value = 0.3463 Odds Ratio & 95% Confidence intervals (Over-dominant model)

Country Odds Ratio Odd ratio 95% CI Weight (%)

Reference
Ghana 1.20 [0.05; 30.07] 11.8
Williams et al. 2004 0.0
Farrag et al. 2011 Egypt
Cameroon 0.91 [0.12; 6.71] 23.2
Ghogomu et al. 2016 7.71 [3.94; 15.08] 50.3
Mehri et al. 2012 Tunisia
South African 11.71 [0.72; 191.33] 14.7
Ranjith et al. 2004 0.0
Tchelougou et al. 2015 Burkina Faso
Nigeria 0.0
Kooffreh et al. 2013
4.01 [1.17; 13.80] 100.0
Random effects model
0.01 0.1 1 10 100
Heterogeneity: I2= 42%, r2= 0.6726, p = 0.16
Egger Test p-value = 0.9779 Odds Ratio & 95% Confidence intervals (Homozygote codominant)

Reference Country Odds Ratio Odd ratio 95% CI Weight (%)

Williams et al. 2004 Ghana 0.60 [0.10; 3.70] 9.0
Farrag et al. 2011 Egypt 0.10 [0.01; 1.08] 6.1
Ghogomu et al. 2016 Cameroon 1.51 [0.27; 8.46] 9.7
Mehri et al. 2012 Tunisia 3.34 [1.80; 6.22] 23.6
Ranjith et al. 2004 South African 1.67 [0.67; 4.21] 18.8
Tchelougou et al. 2015 Burkina Faso 1.01 [0.35; 2.93] 16.7
Kooffreh et al. 2013 Nigeria 1.17 [0.39; 3.50] 16.2
Random effects model 1.30 [0.68; 2.49] 100.0
Heterogeneity: I2= 53%, r2= 0.3663, p = 0.05 0.01 0.1 1 10 100
Egger Test p-value = 0.008043
Odds Ratio & 95% Confidence intervals (Heterozygote codominant)

F I G U R E   2   Forest plot for the effects of rs5186 from different genetic models on the risk of hypertension across studies in Africa. Figures
panels (top to bottom) are for the “alleles contrast,” “dominant,” and “recessive” models of genetic associations, respectively, for the first column,
and “overdominant,” “homozygote codominant,” and “heterozygote codominant” models for the second column. For each figure panel, the black
boxes are for the effect estimates (odd ratio) of the association, and the horizontal bars are for the 95% confidence interval (CI). The sizes of the
boxes are proportional to the inverse variance of the effect estimates. The diamond beneath the black boxes is for the overall effect estimates
across studies, from random effects model meta-­analysis. A dotted vertical line centered on the diamond has been added to assist visual
interpretation. For each contributing study, the odd ratio and 95% CI are also shown, together with the weight (in percentage), reflecting the
contribution of the study to the overall estimates. The horizontal bar (x-­axis) is on log scale to allow a balanced distribution of the CIs around the
effect estimates. The heterogeneity statistics are also shown. ATR1 indicates angiotensin II type 1 receptor
YAKO et al. |
      5

Reference (AGT) Country Odds Ratio Odd ratio 95% CI Weight (%)

Arfa et al. 2010 Tunisia 0.99 [0.47; 2.07] 13.0

Kooffreh et al. 2013 Nigeria 0.32 [0.23; 0.44] 15.6
Mehri et al. 2012 Tunisia 1.70 [1.24; 2.32] 15.7
Naglaa Raafat AbdRaboh et al 2012 Egypt 0.45 [0.30; 0.68] 15.2
Ranjith et al. 2004 South African 1.53 [0.91; 2.58] 14.5
William et al. 2004 Ghanaian 0.73 [0.28; 1.90] 11.4
Tchelougou et al. 2015 Burkina Faso 0.89 [0.53; 1.49] 14.6
Random effects model 0.81 [0.45; 1.46] 100.0
Heterogeneity: I2= 91%, r2= 0.5521, p < 0.01
Egger Test p-value = 0.6829 0.5 1 2
Odds Ratio & 95% Confidence intervals (Allele contrast model)

Reference Country Odds Ratio Odd ratio 95% CI Weight (%)

Arfa et al. 2010 Tunisia 1.35 [0.43; 4.27] 13.2

Kooffreh et al. 2013 Nigeria 0.44 [0.08; 2.40] 6.5
Mehri et al. 2012 Tunisia 2.37 [1.38; 4.07] 40.3
Naglaa Raafat AbdRaboh et al 2012 Egypt 0.92 [0.40; 2.14] 22.0
Ranjith et al. 2004 South African 1.61 [0.48; 5.41] 12.1
William et al. 2004 Ghanaian 0.0
Tchelougou et al. 2015 Burkina Faso 1.49 [0.25; 9.03] 5.9

Random effects model 1.49 [0.95; 2.33] 100.0

Heterogeneity: I2= 17%, r2= 0.0546, p = 0.31 0.1 0.5 1 2 10
Egger Test p-value = 0.1082
Odds Ratio & 95% Confidence intervals (Dominant model)

Reference Country Odds Ratio Odd ratio 95% CI Weight (%)

Arfa et al. 2010 Tunisia 0.69 [0.20; 2.33] 7.9
Kooffreh et al. 2013 Nigeria 0.64 [0.44; 0.93] 19.0
Mehri et al. 2012 Tunisia 1.67 [1.05; 2.68] 17.5
Naglaa Raafat AbdRaboh et al 2012 Egypt 2.29 [1.20; 4.37] 14.7
Ranjith et al. 2004 South African 1.70 [0.89; 3.24] 14.8
William et al. 2004 Ghanaian 0.71 [0.26; 1.92] 10.1
Tchelougou et al. 2015 Burkina Faso 0.84 [0.48; 1.47] 16.1
Random effects model 1.12 [0.73; 1.72] 100.0
Heterogeneity: I2= 70%, r2= 0.2136, p < 0.01
Egger Test p-value = 0.7003 0.5 1 2
Odds Ratio & 95% Confidence intervals (recessive model)

Reference Country Odds Ratio Odd ratio 95% CI Weight (%)

Arfa et al. 2010 Tunisia 1.69 [0.59; 4.85] 7.6

Kooffreh et al. 2013 Nigeria 1.52 [1.04; 2.23] 20.5
Mehri et al. 2012 Tunisia 1.19 [0.77; 1.84] 19.0
Naglaa Raafat AbdRaboh et al 2012 Egypt 0.49 [0.27; 0.87] 15.5
Ranjith et al. 2004 South African 0.67 [0.35; 1.31] 13.5
William et al. 2004 Ghanaian 1.40 [0.52; 3.78] 8.4
Tchelougou et al. 2015 Burkina Faso 1.26 [0.70; 2.24] 15.4

1.06 [0.75; 1.50] 100.0

Random effects model
Heterogeneity: I2= 56%, r2= 0.1128, p = 0.03 0.5 1 2
Egger Test p-value = 0.7064 Odds Ratio & 95% Confidence intervals (Over-dominant model)

Reference Country Odds Ratio Odd ratio 95% CI Weight (%)

Arfa et al. 2010 Tunisia 0.93 [0.22; 3.91] 10.0

Kooffreh et al. 2013 Nigeria 0.42 [0.08; 2.31] 7.3
Mehri et al. 2012 Tunisia 2.77 [1.49; 5.14] 42.5
Naglaa Raafat AbdRaboh et al 2012 Egypt 1.70 [0.65; 4.48] 20.5
Ranjith et al. 2004 South African 1.98 [0.58; 6.83] 13.2
William et al. 2004 Ghanaian 0.0
Tchelougou et al. 2015 Burkina Faso 1.45 [0.24; 8.78] 6.5

Random effects model 1.80 [1.13; 2.87] 100.0

Heterogeneity: I2= 9%, r2= 0.0349, p = 0.36 0.1 0.5 1 2 10
Egger Test p-value = 0.02281
Odds Ratio & 95% Confidence intervals (Homozygote codominant model)

Reference Country Odds Ratio Odd ratio 95% CI Weight (%)

Arfa et al. 2010 Tunisia
Kooffreh et al. 2013 1.63 [0.47; 5.66] 11.6
Nigeria
Mehri et al. 2012 0.64 [0.11; 3.65] 6.1
Tunisia
Naglaa Raafat AbdRaboh et al 2012 2.13 [1.19; 3.80] 43.8
Egypt
Ranjith et al. 2004 0.70 [0.29; 1.66] 22.4
South African
William et al. 2004 1.21 [0.33; 4.37] 10.8
Ghanaian
Tchelougou et al. 2015 0.0
Burkina Faso
1.81 [0.28; 11.75] 5.3
Random effects model
Heterogeneity: I2= 8%, r2= 0.0254, p = 0.37 1.40 [0.90; 2.16] 100.0
Egger Test p-value = 0.3589 0.1 0.5 1 2 10
Odds Ratio & 95% Confidence intervals (Heterozygote codominant model)

F I G U R E   3   Forest plot for the effects of rs699 from different genetic models on the risk of hypertension across studies in Africa. Conventions
are as per Figure 2
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6       YAKO et al.

Reference (ACE) Country Odds Ratio Odd ratio 95% CI Weight (%)

Naglaa Raafat AbdRaboh et al. 2012 Egypt/NR 1.12 [0.76; 1.67] 11.8
Ranjith et al. 2004 South African/Indian 0.76 [0.47; 1.20] 11.3
Tchelougou et al. 2015 Burkina Faso/NR 2.68 [1.95; 3.69] 12.2
Zarouk et al. 2012 Egypt/NR 3.13 [1.41; 6.98] 8.7
Arfa et al. 2010 Tunisia/NR 0.70 [0.34; 1.46] 9.2
Kabadou et al. 2013 Tunisian/NR 0.91 [0.73; 1.12] 12.8
Mehri et al. 2012 Tunisia/NR 2.61 [1.90; 3.58] 12.3
Williams et al. 2004 Ghana 1.21 [0.76; 1.92] 11.3
Zawilla et al. 2014 Egypt/NR 0.56 [0.32; 0.99] 10.5

1.27 [0.85; 1.89] 100.0

Random effects model
Heterogeneity: I2 = 89, r2= 0.316, p < 0.01 0.2 0.5 1 2 5
Odds Ratio & 95% Confidence intervals (Allele contrast model)
Egger Test p-value = 0.8904

Reference Country Odds Ratio Odd ratio 95% CI Weight (%)

Naglaa Raafat AbdRaboh et al. 2012 Egypt/NR 1.14 [0.54; 2.40] 13.6
Ranjith et al. 2004 South African/Indian 0.60 [0.32; 1.15] 14.4
Tchelougou et al. 2015 Burkina Faso/NR 2.93 [1.38; 6.22] 13.5
Zarouk et al. 2012 Egypt/NR 7.60 [1.38; 41.95] 7.3
Arfa et al. 2010 Tunisia/NR 0.25 [0.05; 1.21] 8.0
Kabadou et al. 2013 Tunisian/NR 0.93 [0.58; 1.48] 15.5
Mehri et al. 2012 Tunisia/NR 3.86 [2.21; 6.72] 15.0
Williams et al. 2004 Ghana 2.20 [0.92; 5.24] 12.7
Zawilla et al. 2014 Egypt/NR 0.0

1.52 [0.82; 2.80] 100.0

Random effects model
0.1 0.5 1 2 10
Heterogeneity: I2= 80%, r2= 0.5725, p < 0.01
Egger Test p-value = 0.9628 Odds Ratio & 95% Confidence intervals (Dominant model)

Reference Country Odds Ratio Odd ratio 95% CI Weight (%)

Naglaa Raafat AbdRaboh et al. 2012 Egypt/NR 1.22 [0.66; 2.24] 11.6
Ranjith et al. 2004 South African/Indian 0.88 [0.36; 2.17] 9.7
Tchelougou et al. 2015 Burkina Faso/NR 3.62 [2.40; 5.45] 12.8
Zarouk et al. 2012 Egypt/NR 3.00 [0.99; 9.07] 8.4
Arfa et al. 2010 Tunisia/NR 1.11 [0.39; 3.14] 8.8
Kabadou et al. 2013 Tunisian/NR 0.86 [0.66; 1.14] 13.5
Mehri et al. 2012 Tunisia/NR 3.10 [1.88; 5.11] 12.3
Williams et al. 2004 Ghana 0.94 [0.47; 1.91] 11.0
Zawilla et al. 2014 Egypt/NR 0.53 [0.29; 0.97] 11.7

Random effects model 1.37 [0.83; 2.28] 100.0

Heterogeneity: I2= 86%, r2= 0.479, p < 0.01
Egger Test p-value = 0.941 0.2 0.5 1 2 5
Odds Ratio & 95% Confidence intervals (Recessive model)

Reference Country Odds Ratio

Odd ratio 95% CI Weight (%)
Naglaa Raafat AbdRaboh et al. 2012 Egypt/NR 0.91 11.8
[0.52; 1.59]
Ranjith et al. 2004 South African/Indian 0.67 10.9
[0.35; 1.26]
Tchelougou et al. 2015 Burkina Faso/NR 0.38 13.5
[0.25; 0.57]
Zarouk et al. 2012 Egypt/NR 0.88 [0.29; 2.61] 6.6
Arfa et al. 2010 Tunisia/NR 0.40 7.1
[0.14; 1.13]
Kabadou et al. 2013 Tunisian/NR 1.13 14.9
[0.86; 1.49]
Mehri et al. 2012 Tunisia/NR 1.10 13.2
[0.71; 1.70]
Williams et al. 2004 Ghana 1.60 [0.83; 3.08] 10.7
Zawilla et al. 2014 Egypt/NR 1.88 11.3
[1.03; 3.41]

Random effects model 0.90 [0.62; 1.30] 100.0

Heterogeneity: I2 = 75%, r2 = 0.2143, = , p < 0.01 0.2 0.5 1 2 5
Egger Test p-value = 0.8899 Odds Ratio & 95% Confidence intervals (Over-dominant model)

Reference Country Odds Ratio Odd ratio 95% CI Weight (%)

Naglaa Raafat AbdRaboh et al. 2012 Egypt/NR 1.28 [0.54; 3.01] 13.5
Ranjith et al. 2004 South African/Indian 0.65 [0.25; 1.72] 12.8
Tchelougou et al. 2015 Burkina Faso/NR 4.99 [2.29; 10.89] 13.9
Zarouk et al. 2012 Egypt/NR 10.29 [1.69; 62.74] 8.4
Arfa et al. 2010 Tunisia/NR 0.34 [0.06; 1.85] 8.9
Kabadou et al. 2013 Tunisian/NR 0.87 [0.53; 1.41] 15.3
Mehri et al. 2012 Tunisia/NR 6.20 [3.23; 11.90] 14.5
Williams et al. 2004 Ghana 1.87 [0.70; 4.98] 12.8
Zawilla et al. 2014 Egypt/NR 0.0

1.87 [0.88; 3.95] 100.0

Random effects model
Heterogeneity: I2 = 83%, r2 = 9022 = , p < 0.01 0.1 0.5 1 2 10
Egger Test p-value = 0.9695 Odds Ratio & 95% Confidence intervals (Homozygote codominant)

Odds Ratio
Reference Country Odd ratio 95% CI Weight (%)

Naglaa Raafat AbdRaboh et al. 2012 Egypt/NR 1.07 [0.49; 2.32] 13.8
Ranjith et al. 2004 South African/Indian 0.59 [0.30; 1.17] 14.8
Tchelougou et al. 2015 Burkina Faso/NR 1.48 [0.67; 3.27] 13.6
Zarouk et al. 2012 Egypt/NR 5.25 [0.85; 32.43] 5.8
Arfa et al. 2010 Tunisia/NR 0.19 [0.04; 1.00] 6.6
Kabadou et al. 2013 Tunisian/NR 1.00 [0.62; 1.63] 17.0
Mehri et al. 2012 Tunisia/NR 2.90 [1.60; 5.23] 15.9
Williams et al. 2004 Ghana 2.42 [0.97; 6.04] 12.4
Zawilla et al. 2014 Egypt/NR 0.0

1.28 [0.76; 2.16] 100.0

Random effects model
0.1 0.5 1 2 10
Heterogeneity: I2 = 69%, r2 = 3527 = , p < 0.01 Odds Ratio & 95% Confidence intervals (Heterozygote codominant)
Egger Test p-value = 0.8958

F I G U R E   4   Forest plot for the effects of rs4340 from different genetic models on the risk of hypertension across studies in Africa.
Conventions are as per Figure 2
YAKO et al. |
      7

3.4 | Meta-­analysis
Meta-­analysis was possible for only three SNPs within the ACE, AGT,
and AGTR1, respectively, rs4340, rs699, and rs5186 (Figures 2–4).
These are the SNPs that were investigated by more than three dif-
ferent studies (Table 1). Details of these studies are summarized in
Table 1 and Table S4.
Meta-­
analysis of rs5186 included seven studies totaling the
number of cases and controls to 1229 and 1626, respectively. There
was evidence of an association between rs5186 and hypertension
under allele contrast (OR, 1.63; 95% CI, 1.04–2.54) and homozy-
gous codominant (OR, 4.01; 95% CI, 1.17–13.80) models (Figure 2).
Sensitivity analyses suggested that these significant pooled estimates
were driven by the effects of Mehri42 and Ranjith28 and colleagues
since the pooled estimates for both models were nonsignificant each
time one of the two studies was omitted (Figure S1). There was ev-
idence of substantial heterogeneity for the alleles contrast (P = .03)
and dominant models (P < .01), driven by the study by Mehri and as-
sociates42 (Figure S1), and for the recessive model (P = .03), driven by
the study by Goghomu and coworkers36 The Egger test was in favor
of significant publication bias for the dominant model (P = .005) and
heterozygote codominant model (P = .008). For both models, the trim-­
and-­fill method imputed four studies with unrealistic effect estimates
(OR ranging from 5.65 to 106.2) (Figure S4). There was a lack of infor-
mation about genotyping quality control and controlling for population
stratification and therefore likelihood of bias. The significant deviation
from HWE of the distribution of genotypes (P < .0001 in Ghanaian and
Cameroonian populations) indicates an existence of genotyping error.
We provided Venice grading ABB or moderate epidemiological credi-
bility for this meta-­analysis (Table 2).
The rs699 meta-­analysis included seven studies with a total of
1257 cases and 1710 controls. An association between rs699 and hy-
pertension was observed for the homozygous codominant model (OR,
1.80; 95% CI, 1.13–2.87), with no evidence of statistical heterogeneity

T A B L E   1   Genotype frequency distribution of the rs4340, rs5186, and rs699 in African populations

Genotypes, no hypertension,
Reference Country Genotypes, hypertension, No. HWE (P value) No. HWE (P value)

rs5186 AA AC CC AA AC CC
27
Williams et al Ghana 113 3 1 <.0001 45 2 0 .882
Farrag et al34 Egypt 39 1 0 .936 12 3 0 .667
36
Ghogomu et al Cameroon 2 67 5 <.0001 4 89 11 <.0001
Mehri et al42 Tunisia 17 63 62 .871 74 82 35 .151
28
Ranjith et al South African 35 6 1 .268 410 42 1 .950
Tchelougou et al58 Burkina Faso 195 7 0 .802 197 7 0 .803
59
Kooffreh et al Nigeria 605 7 0 .887 606 6 0 .906

rs699 MM MT TT MM MT TT
32
Arfa et al Tunisia 10 21 8 .618 7 9 6 .398
29
Kooffreh et al Nigeria 4 67 541 .232 2 52 642 .391
Mehri et al60 Tunisia 23 67 52 .856 60 82 49 .056
30
AbdRaboh et al Egypt 14 57 39 .330 11 64 18 .0002
Ranjith et al28 South African 3 14 25 .599 50 193 210 .573
27
William et al Ghana 0 18 92 .350 0 6 43 .648
Tchelougou et al58 Burkina Faso 2 29 171 .541 3 24 177 .051

rs4340 II ID DD DD DI II
30
AbdRaboh et al Egypt 17 59 34 .299 25 52 16 .214
28
Ranjith et al South African 18 18 6 .666 72 240 141 .071
Tchelougou et al58 Burkina Faso 10 57 135 .225 73 104 27 .289
61
Zarouk et al Egypt 2 14 24 .982 7 8 6 .279
Arfa et al32 Tunisia 14 16 19 .017 8 12 2 .402
Kabadou et al23 Tunisian 39 176 173 .553 205 180 40 .957
Mehri et al60 Tunisia 20 65 57 .832 34 83 74 .208
William et al27 Ghana 14 74 38 .014 16 24 11 .723
Zawilla et al62 Egypt NA 21 78 .238 244 35 NA .264

HWE, Hardy-­Weinberg equilibrium.

 |
8       YAKO et al.

between studies (I2 = 9%) (Figure 3). In sensitivity analyses, this effect

Overall rating
estimate was enhanced when findings reported by Arfa32 or Kooffreh29

Moderate

Moderate
and colleagues were omitted (Figure S2). In similar analyses, omitting

Weak
AbdRaboh and colleagues30 led to a significant pooled estimate for the
dominant model (OR, 1.83; 95% CI, 1.20–2.81 [I2 = 0]), for the over-
dominant model (OR, 1.26; 95% CI, 1.00–1.58 [I2 = 0]), and for the

Venice interim
heterozygote codominant model (OR, 1.75; 95% CI, 1.11–2.75 [I2 = 0])
(Figure S2). There was significant publication bias (P = .023) for the
homozygous codominant model. The trim-­and-­fill methods imputed

rating

ACA
AAB
ABB
three studies with effect size (OR) ranging from 3.76 to 12.94 and a
resulting pooled estimate of 2.27 (1.33–3.85, heterogeneity P = .14))
(Figure S5). The significant P value of the Egger test and lack of report-

Risk of population
ing on adjusting for population stratification prompted us to grade this

stratification
meta-­analysis AAB or moderate epidemiological credibility (Table 2).
No deviation from HWE was found in studies included in this meta-­
analysis (P > .2).

Yes

Yes

Yes
Pooled data on rs4340 included 1198 cases and 1740 controls and
suggested no evidence of association with hypertension across the six

from HWE
genetic models (Figure 4). There was substantial heterogeneity across

Deviation

studies)

studies)
Yes (two

Yes (two
studies in all models (all heterogeneity P < .01), not accounted for by a

No
particular study in sensitivity analysis (Figure S3). For the homozygote
codominant models, the pooled estimate reached statistical signifi-
cance when Kabadou and colleagues23 was dropped, with an OR of

quality control

Not reported

Not reported

Not reported
2.14 (95% CI, 1.01–4.77; I2 = 0.84) (Figure S3). There was no evidence

Genotyping
of publication bias (all P > .890 for the Egger test). The trim-­and-­fill
methods imputed two studies (OR ranging from 3.13 to 3.35) for the
overdominant model, and one study (OR, 0.28) for the homozygote Pooled sample
codominant model, but the resulting pooled estimates were always
nonsignificant (Figure S6). Although there was no evidence of publica-

DBP, diastolic blood pressure; HWE, Hardy-­Weinberg equilibrium, SBP, systolic blood pressure.
tion bias, these studies failed to report on the quality control of geno-
2855

2967

2938
size

typing methods, and the population stratification was not accounted

for, thus the weak (ACA) Venice interim grading. Deviation from
T A B L E   2   Venice interim assessments of the credibility of each meta-­analysis

HWE was found in the Tunisian and Ghanaian hypertension groups

Studies, No.

(P = .017) that were included in the studies by Arfa32 and Williams27

and colleagues, respectively.
7

4 |  DISCUSSION
Hypertension (SBP >140 mm Hg and/or DBP

Hypertension (SBP >140 mm Hg and/or DBP

Hypertension (SBP >140 mm Hg and/or DBP

Heterogeneous susceptibility to hypertension among different

populations has been largely documented. This has been particu-
>90 mm Hg, doctor diagnosis)

>90 mm Hg, doctor diagnosis)

>90 mm Hg, doctor diagnosis)

larly noted in the United States, with studies demonstrating that

African Americans generally have higher BP levels and are char-
acterized by early-­onset hypertension compared with other eth-
nic groups.43 Susceptibility to hypertension is influenced, in part,
by variations in regulation of body salt and water among many
Phenotype

population groups. One of the well-­studied pathways involved

in regulation of thirst and sodium homeostasis is the RAAS, and
genetic variants have been extensively investigated in relation to
hypertension.44,45
Studies conducted in Africa so far generally lack the power to de-
rs5186

rs4340
rs699

tect statistically significant association between SNPs and complex dis-

SNP

eases, as we observed in this review. We conducted meta-­analyses of

YAKO et al.
three SNPs in three genes of the RAAS: ACE I/D (rs4340), AGT M235T
(rs699), and AGTR1 1166A>C (rs5186) to achieve an optimum power.
We observed an association between rs5186 and hypertension, which
is in contrast to findings from a meta-­analysis by Liu and cowork-
ers46 in African Americans. Instead, Liu and associates46 observed the
rs5186-­hypertension association in Asians and Caucasians in support
of findings reported elsewhere.45,47 Our meta-­analysis also suggests an
association of rs699 with hypertension, similar to studies conducted
in Asians,48,49 while no association between any of the common SNPs
found in RAAS genes and hypertension has been reported by other
authors.50 The inconsistent findings may be attributable to differences
in study design, specifically generalization of hypertension by some
studies as hypertension,45–47 while Sun and colleagues50 investigated
the salt-­sensitive hypertension phenotype. Regulation of BP in the
presence or absence of salt sensitivity varies considerably among in-
dividuals within the same or in different ethnic population groups, and
this may also contribute to the lack of consistent associations reported
by many studies.
The role of AGTR1 and AGT in hypertension has also been high-
lighted in patients with renal cell cancer, in whom a significant inter-
action with hypertension was observed.51 Similar to many studies,52
our meta-­analysis found no association between rs4340 and hyper-
tension. In contrast, other studies have reported the association of
rs4340 with hypertension.53 Decker and coworkers51 on the other
hand found an interaction between ACE and sodium intake, an associ-
ation that may also be involved in hypertension occurrence. In light of
these findings, the role of ACE in hypertension may not be ruled out in
African populations, as our meta-­analysis considered one ACE SNP but
not its interaction with sodium intake.
The mechanism underlying rs5186-­hypertension association
is unclear as the SNP is located within the 3′ untranslated re-
gion of AGTR1. It is possible that rs5186 is in linkage disequi-
librium with other functional polymorphisms. Alternatively, this
SNP may be involved in regulation of AGTR1 expression. Despite
the elusive function of the rs5186 SNP, the AGTR1 has been
selected as the potential treatment target for hypertension be-
cause of its evident association with hypertension in certain
population groups 46 and effectiveness of its antagonists as anti-
hypertensive therapy. 54 However, BP-­lowering efficacy of RAAS
inhibitors is not evident in African Americans, probably because
of their low renin profile and sensitivity to salt intake. 55 Similarly,
black populations in Africa have a characteristic salt-­s ensitive
hypertension 56 and may be less responsive to RAAS inhibitors. It
is also important to consider that antihypertensive therapy may
be influenced by the presence or absence of polymorphisms in
RAAS genes. For example, Woodiwiss and coworkers 57 demon-
strated that genotypes of the functional SNPs in AGT contrib-
uted to the variability of antihypertensive responses to ACE
inhibitors in individuals of African ancestry. This study, there-
fore, highlights the importance of investigating sequence vari-
ations in the RAAS genes that may be involved in hypertension
occurrence and those that may affect response to treatments in
African populations.
|
      9
5 | STUDY LIMITATIONS AND STRENGTHS
We found moderate heterogeneity among studies included in our
meta-­analysis, particularly for the rs5186 SNP. This may be at-
tributable to heterogeneous populations of the studies included
in the meta-­analysis, which included Arabs, Indians, and black and
Caucasian Africans. Furthermore, deviation from HWE in two popu-
lation groups might have contributed to the existing heterogene-
ity. The studies included and our meta-­analysis did not address the
presence of population stratification. Our review has other limita-
tions, such as selective reporting of methodological aspects. Not
all of the studies included reported sample size calculation, HWE,
and adjustment of confounders. The sample sizes of selected stud-
ies were relatively small. Furthermore, the definition of hyperten-
sion varied among studies. This may have hampered identification
of small effects of other polymorphisms investigated. Our meta-­
analysis was also hindered by the small number of genetic asso-
ciation studies conducted in Africa. Only three SNPs have been
investigated by more than three African studies. Our study also
has several strengths. This is the first systematic review and meta-­
analysis of genetic association studies conducted in African pop-
ulations residing in Africa. We extensively appraised the existing
studies using appropriate protocols designed for genetic association
studies. We increased the likelihood of detecting significant effects
across studies by conducting a meta-­analysis under several genetic
models, using the Venice interim criteria to assess the quality of
studies included.
6 | CONCLUSIONS
Our study findings suggest that, to date, only two SNPs of the AGT
(rs699) and AGTR1 (rs5186) are likely to predispose African popula-
tions to hypertension, necessitating further investigation in larger-­
scale genetic studies so that more susceptibility polymorphisms
specific to African populations can be discovered.
CO NFL I C T O F I NT ER ES T
The authors have no conflicts of interest to declare.
O RC I D
Andre P. Kengne  http://orcid.org/0000-0002-5183-131X
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How to cite this article: Yako YY, Balti EV, Matsha TE, et al.
Genetic factors contributing to hypertension in African-­based
populations: A systematic review and meta-­analysis. J Clin
Hypertens. 2018;00:1–11. https://doi.org/10.1111/jch.13225