Pharmacogenomic Genome-Wide Meta-Analysis of Blood Pressure Response to β-Blockers in Hypertensive African Americans

Abstract

African Americans suffer a higher prevalence of hypertension compared to other racial/ethnic groups. In this study, we performed a pharmacogenomics genome-wide association study of blood pressure response to β-blockers in African Americans with uncomplicated hypertension. Genome-wide meta-analysis was performed in 318 African American hypertensive participants in the two Pharmacogenomic Evaluation of Antihypertensive Responses studies: 150 treated with atenolol monotherapy and 168 treated with metoprolol monotherapy. The analysis adjusted for age, gender, baseline BP and principal components for ancestry. Genome-wide significant variants with p < 5*10−8 and suggestive variants with p < 5*10−7 were evaluated in an additional cohort of 141 African Americans treated with the addition of atenolol to hydrochlorothiazide treatment. The validated variants were then meta-analyzed in these 3 groups of African Americans. Two variants discovered in the monotherapy meta-analysis were validated in the add-on therapy. African American participants heterozygous for SLC25A31 rs201279313 deletion vs wild-type genotype had better diastolic blood pressure response to atenolol monotherapy, metoprolol monotherapy and atenolol add-on therapy: −9.3 vs. −4.6, −9.6 vs. −4.8 and −9.7 vs. −6.4 mmHg, respectively (3-group meta-analysis p= 2.5*10−8, beta = −4.42 mmHg per variant allele). Similarly, LRRC15 rs11313667 was validated for systolic blood pressure response to β-blocker therapy with 3-group meta-analysis p = 7.2 *10−8 and beta = −3.65 mmHg per variant allele. In this first pharmacogenomics genome-wide meta-analysis of BP response to β-blockers in African Americans, we identified novel variants that may provide valuable information for personalized antihypertensive treatment in this group.

Race and sex differences in cardiovascular α-adrenergic and β-adrenergic receptor responsiveness in men and women with high blood pressure

“…Growing evidence indicates that adrenergic receptor density, distribution and function, and consequent vasomotor activity are determined in part by genetics, accounting for some of the individual differences both between and within racial groups [34,35]. A recent pharmacogenomics genome-wide meta-analysis of BP responses to β-blockers in African-Americans showed that two genotype variants were related to the antihypertensive efficacy of atenolol and metoprolol [36]. A study examining the effects of β 1 -adrenergic receptor polymorphisms on the response to β-blockade, however, found that racial differences could not be fully explained by different distributions of functional β 1 -adrenergic receptor variants [37].…”

A Physiologic Approach to the Pharmacogenomics of Hypertension

“…A GWAS of atenolol and metoprolol BP response was conducted in a cohort of AfricanAmerican, hypertensive participants from the PEAR studies 85 . Two replicated variants, rs201279313 in SLC25A31 and rs11313667 in LRRC15, were found to predict improved BP response to β-blocker monotherapy in African Americans.…”

Personalized medicine: Genetic risk prediction of drug response

“…changes in diet, exercise, time-of-day, combinations of prescribed drugs, alcohol usage, etc .). Several PGx GWAS have reported variants in plausible genes associated with thiazide diuretics (Chittani et al, 2015; Turner et al, 2008; Turner et al, 2013), angiotensin II receptor blockers (Frau et al, 2014; Turner et al, 2012), and beta-blockers (Gong et al, 2015; Gong et al, 2016); yet, most of these studies involve relatively small discovery sample-sizes and are underpowered, as far as detecting associations having genome-wide significance ( i.e. P < 5 × 10 −8 ).…”