Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.
ABSTRACT: The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
Project description:Vitamin D reportedly influences vascular function, which is worse in African Americans (AAs) relative to European Americans (EAs). It is not clear if ethnic differences in 25(OH)D mediate differences in vascular function. This study examined the relationships of serum 25-hydroxyvitamin D (25(OH)D) with indicators of vascular function among healthy, young AA and EA adults.This is a cross sectional study involving 23 AAs and 22 EAs. The main outcomes were augmentation index (AIx75), central aortic pressure, pulse wave velocity (PWV), flow-mediated dilation (FMD), and seated and supine blood pressures.Results indicated that 25(OH)D was inversely associated with AIx75, supine systolic blood pressure (SBP), central aortic SBP and central aortic diastolic blood pressure (DBP), independent of age, sex, and percent body fat (standardized β= -0.29 to -0.43, P < 0.05 for all). AAs had greater AIx75 (P = 0.04) and PWV (P = 0.07) and lower FMD (P = 0.02) compared to EA after adjusting for age and percent body fat; further adjustment for 25(OH)D reduced the ethnic differences (P = 0.44, 0.53, and 0.20, respectively).The 25(OH)D was associated with vascular function in healthy adults, and lower 25(OH)D among AAs may contribute to their greater arterial stiffness and reduced endothelial function (Clinical trials.gov NCT01041365, NCT01041547).
Project description:Prostasin, a serine protease, is suggested to be a novel mechanism regulating the epithelial sodium channel (ENaC) expressed in the distal nephron. This study aimed to evaluate whether the human prostasin gene is a novel candidate gene underlying blood pressure (BP) elevation.In a sample of healthy African-American (AA) and European-American (EA) twin subjects aged 17.6 +/- 3.3 years (n = 920, 45% AAs), race-specific tagging single-nucleotide polymorphisms (tSNPs) were identified to tag all the available SNPs +/- 2 kb up- and downstream of the prostasin gene from HapMap at r2 of 0.8-1.0. Selection yielded four tSNPs in AAs and one in EAs, with one tSNP (rs12597511: C to T) present in both AAs and EAs.For rs12597511, CT and TT genotypes exhibited higher systolic BP (SBP) than CC genotype (115.9 +/- 1.1 mm Hg vs. 113.7 +/- 0.6 mm Hg, P = 0.025 (AAs); and 110.7 +/- 0.5 mm Hg vs. 109.6 +/- 0.6 mm Hg, P = 0.115 (EAs)). CT and TT genotypes compared with CC genotype showed a significant increase in diastolic BP (DBP) in both racial groups (62.5 +/- 0.7 mm Hg vs. 60.4 +/- 0.4 mm Hg, P = 0.003 (AAs); and 58.2 +/- 0.3 mm Hg vs. 56.7 +/- 0.4 mm Hg, P = 0.007 (EAs)). Furthermore, there was an increase in radial pulse wave velocity (PWV) in subjects with CT and TT genotype as compared with those with CC genotype (6.5 +/- 0.1 vs. 6.1 +/- 0.1 m/s, P < 0.0001) (EAs); and 6.7 +/- 0.1 vs. 6.6 +/- 0.1 m/s, P = 0.354 (AAs)). Analyses combining AAs and EAs consistently demonstrated a statistical significance of rs12597511 on all the phenotypes including SBP/DBP and PWV.Genetic variation of the prostasin gene may be implicated in the development of hypertension in youths..
Project description:Both genomics and environmental stressors play a significant role in increases in blood pressure (BP). In an attempt to further explain the hypertension (HTN) disparity among African Americans (AA), both genetic underpinnings (selected candidate genes) and stress due to perceived racial discrimination (as reported in the literature) have independently been linked to increased BP among AAs. Although Gene x Environment interactions on BP have been examined, the environmental component of these investigations has focused more on lifestyle behaviors such as smoking, diet, and physical activity, and less on psychosocial stressors such as perceived discrimination.The present study uses candidate gene analyses to identify the relationship between Everyday Discrimination (ED) and Major Life Discrimination (MLD) with increases in systolic BP (SBP) and diastolic BP (DBP) among AA in the Jackson Heart Study. Multiple linear regression models reveal no association between discrimination and BP after adjusting for age, sex, body mass index (BMI), antihypertensive medication use, and current smoking status.Subsequent candidate gene analysis identified 5 SNPs (rs7602215, rs3771724, rs1006502, rs1791926, and rs2258119) that interacted with perceived discrimination and SBP, and 3 SNPs (rs2034454, rs7602215, and rs3771724) that interacted with perceived discrimination and DBP. Most notably, there was a significant SNP?×?discrimination interaction for 2 SNPs on the SLC4A5 gene: rs3771724 (MLD: SBP P = .034, DBP P = .031; ED: DBP: P = .016) and rs1006502 (MLD: SBP P?=?.034, DBP P?=?.030; ED: DBP P?=?.015).This study supports the idea that SNP?×?discrimination interactions combine to influence clinically relevant traits such as BP. Replication with similar epidemiological samples is required to ascertain the role of genes and psychosocial stressors in the development and expression of high BP in this understudied population.
Project description:Blood pressure (BP) is significantly influenced by genetic factors; however, less than 3% of the BP variance has been accounted for by variants identified from genome-wide association studies (GWAS) of primarily European-descent cohorts. Other genetic influences, including gene-environment (GxE) interactions, may explain more of the unexplained variance in BP. African Americans (AA) have a higher prevalence and earlier age of onset of hypertension (HTN) as compared with European Americans (EA); responses to anti-hypertensive drugs vary across race groups. To examine potential interactions between the use of loop diuretics and HTN traits, we analyzed systolic (SBP) and diastolic (DBP) blood BP from 1222 AA and 1231 EA participants in the Hypertension Genetic Epidemiology Network (HyperGEN). Population-specific score tests were used to test associations of SBP and DBP, using a panel of genotyped and imputed single nucleotide polymorphisms (SNPs) for AA (2.9 million SNPs) and EA (2.3 million SNPs). Several promising loci were identified through gene-loop diuretic interactions, although no SNP reached genome-wide significance after adjustment for genomic inflation. In AA, SNPs in or near the genes NUDT12, CHL1, GRIA1, CACNB2, and PYHIN1 were identified for SBP, and SNPs near ID3 were identified for DBP. For EA, promising SNPs for SBP were identified in ESR1 and for DBP in SPATS2L and EYA2. Among these SNPs, none were common across phenotypes or population groups. Biologic plausibility exists for many of the identified genes, suggesting that these are candidate genes for regulation of BP and/or anti-hypertensive drug response. The lack of genome-wide significance is understandable in this small study employing gene-drug interactions. These findings provide a set of prioritized SNPs/candidate genes for future studies in HTN. Studies in more diversified population samples may help identify previously missed variants.
Project description:The effects of alcohol dehydrogenase (ADH) 2 and aldehyde dehydrogenase (ALDH) 2 genotypes on the alcohol-blood pressure association are unclear. We examined the association of ADH2 or ALDH2 genotypes with blood pressure in older Chinese men. Based on the Guangzhou Biobank Cohort Study (GBCS), 4792 men with valid ADH2, ALDH2 genotypes were included, and genotyping of rs1229984 ADH2 and rs671 ALDH2 (AA, AG/GA or GG) was performed using a Sequenom Mass-Array platform. Information on socio-demographics and lifestyle factors, including alcohol use, was obtained from a questionnaire, and blood pressure was measured. Among alcohol drinkers, systolic and diastolic blood pressure (SBP and DBP) and mean arterial pressure (MAP) were highest for men with the GG ADH2 genotype (136.6, 77.9 and 97.5?mm?Hg, respectively), followed by those with the (AA/AG ADH2+GG ALDH2) genotype (133.4, 77.6 and 96.2?mm?Hg, respectively) and then the (AA/AG ADH2+AA/AG ALDH2) genotype (SBP=132.6, DBP=76.6 and MAP=95.2?mm?Hg) (P for trend ranged 0.025-0.035). After adjustment for potential confounders, as well as frequency or amount of alcohol use, men with the GG ADH2 genotype were more likely to have hypertension (odds ratio (OR)=1.62, 95% confidence interval 1.15-2.28) as were men with the (AA/AG ADH2+AA/AG ALDH2) genotype (OR=1.40, 95% confidence interval 1.01-1.96) compared with men with the (AA/AG ADH2+GG ALDH2) genotype). ADH2 or ALDH2 genotypes were unrelated to hypertension among those who never drink alcohol. ADH2 genotype influences blood pressure and risk of hypertension among male alcohol drinkers, suggesting that the hypertensive effect of alcohol is due to ethanol rather than acetaldehyde.
Project description:BACKGROUND:Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood. METHODS:Using systematic-phased approach, PRA's clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed. RESULTS:EAs with PRA < 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by -15.9 mm Hg, adjusted P < 0.0001), whereas those with PRA ? 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ? 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%. CONCLUSIONS:PRA at the previously established 0.60-0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs. TRIAL REGISTRATION:NCT01203852, NCT00246519, NCT00005520.
Project description:Blood pressure (BP) is a heritable trait with multiple environmental and genetic contributions, with current heritability estimates from twin and family studies being ~ 40%. Here, we use genome-wide polymorphism data from the Atherosclerosis Risk in Communities (ARIC) study to estimate BP heritability from genomic relatedness among cohort members. We utilized data on 6,365,596 and 9,578,528 genotyped and imputed common single nucleotide polymorphisms (SNPs), in 8,901 European ancestry (EA) and 2,860 African Ancestry (AA) ARIC participants, respectively, and a mixed linear model for analyses, to make four observations. First, for BP measurements, the heritability is ~20%/~50% and ~27%/~39% for systolic (SBP)/diastolic (DBP) blood pressure in European and African ancestry individuals, respectively, consistent with prior studies. Second, common variants with allele frequency >10% recapitulate most of the BP heritability in these data. Third, the vast majority of BP heritability varies by chromosome, depending on its length, and is largely concentrated in noncoding genomic regions annotated as DNaseI hypersensitive sites (DHSs). Fourth, the majority of this heritability arises from loci not harboring currently known cardiovascular and renal genes. Recent meta-analyses of large-scale genome-wide association studies (GWASs) and admixture mapping have identified ~50 loci associated with BP and hypertension (HTN), and yet they account for only a small fraction (~2%) of the heritability.
Project description:The Angiotensin-Converting Enzyme-2 (ACE2) gene, located on chromosome X, is believed to be implicated in blood pressure regulation. However the few studies that have examined this association have yielded mixed results. The objective of this study was to assess the association between tag single nucleotide polymorphisms (SNPs) in the angiotensin-converting enzyme-2 gene with blood pressure and blood pressure change in adolescents.Participants in the Nicotine Dependence in Teens (NDIT) cohort study with blood or saliva samples and at least 3 blood pressure measurements over 5 years were included in the analytic sample (n?=?555). Linear growth curve models stratified on sex and ethnicity were used to assess the association between four tag SNPs in the ACE2 gene and systolic (SBP) and diastolic blood pressure (DBP), and blood pressure change.In males of European descent, rs2074192 and rs233575 were significantly associated with SBP and DBP, and rs2158083 was associated with SBP. In French Canadian males, rs233575 and rs2158083 were significantly associated with DBP. Among females of European descent, rs2074192, rs233575, and rs2158083 were significantly associated with change in SBP over 5 years.This is the first study to assess the association between the ACE2 gene with blood pressure and blood pressure change in a cohort of adolescents. Results indicate that several ACE2 gene SNPs are associated with blood pressure or blood pressure change in persons of European descent. However the therapeutic potential of these SNPs should be explored.
Project description:BACKGROUND:African Americans (AA) are disproportionately affected by hypertension-related health disparities. Apolipoprotein L1 (APOL1) risk variants are associated with kidney disease in hypertensive AAs. OBJECTIVES:This study assessed the APOL1 risk alleles' association with blood pressure traits in AAs. METHODS:The discovery cohort included 5,204 AA participants from Mount Sinai's BioMe biobank. Replication cohorts included additional BioMe (n = 1,623), Vanderbilt BioVU (n = 1,809), and Northwestern NUgene (n = 567) AA biobank participants. Single nucleotide polymorphisms determining APOL1 G1 and G2 risk alleles were genotyped in BioMe and imputed in BioVU/NUgene participants. APOL1 risk alleles' association with blood pressure-related traits was tested in the discovery cohort, a meta-analysis of replication cohorts, and a combined meta-analysis under recessive and additive models after adjusting for age, sex, body mass index, and estimated glomerular filtration rate. RESULTS:There were 14% to 16% of APOL1 variant allele homozygotes (2 copies of G1/G2) across cohorts. APOL1 risk alleles were associated under an additive model with systolic blood pressure (SBP) and age at diagnosis of hypertension, which was 2 to 5 years younger in the APOL1 variant allele homozygotes (Cox proportional hazards analysis, p value for combined meta-analysis [pcom] = 1.9 × 10-5). APOL1 risk alleles were associated with overall SBP (pcom = 7.0 × 10-8) and diastolic blood pressure (pcom = 2.8 × 10-4). After adjustment for all covariates, those in the 20- to 29-year age range showed an increase in SBP of 0.94 ± 0.44 mm Hg (pcom = 0.01) per risk variant copy. APOL1-associated estimated glomerular filtration rate decline was observed starting a decade later in life in the 30- to 39-year age range. CONCLUSIONS:APOL1 risk alleles are associated with higher SBP and earlier hypertension diagnoses in young AAs; this relationship appears to follow an additive model.
Project description:OBJECTIVES:African-Americans (AAs) have a high prevalence of hypertension and their blood pressure (BP) control on treatment still lags behind other groups. In 2004, NHLBI funded five projects that aimed to evaluate clinically feasible interventions to effect changes in medical care delivery leading to an increased proportion of AA patients with controlled BP. Three of the groups performed a pooled analysis of trial results to determine: 1) the magnitude of the combined intervention effect; and 2) how the pooled results could inform the methodology for future health-system level BP interventions. METHODS:Using a cluster randomized design, the trials enrolled AAs with uncontrolled hypertension to test interventions targeting a combination of patient and clinician behaviors. The 12-month Systolic BP (SBP) and Diastolic BP (DBP) effects of intervention or control cluster assignment were assessed using mixed effects longitudinal regression modeling. RESULTS:2,015 patients representing 352 clusters participated across the three trials. Pooled BP slopes followed a quadratic pattern, with an initial decline, followed by a rise toward baseline, and did not differ significantly between intervention and control clusters: SBP linear coefficient = -2.60±0.21 mmHg per month, p<0.001; quadratic coefficient = 0.167± 0.02 mmHg/month, p<0.001; group by time interaction group by time group x linear time coefficient=0.145 ± 0.293, p=0.622; group x quadratic time coefficient= -0.017 ± 0.026, p=0.525). RESULTS were similar for DBP. The individual sites did not have significant intervention effects when analyzed separately. CONCLUSION:Investigators planning behavioral trials to improve BP control in health systems serving AAs should plan for small effect sizes and employ a "run-in" period in which BP can be expected to improve in both experimental and control clusters.