The role of SNP-loop diuretic interactions in hypertension across ethnic groups in HyperGEN

Lisa De Las Fuentes,Yun Ju Sung,Sonia Kalathiveetil,D C Rao,Steven C Hunt,Donna K Arnett,Karen L Schwander

doi:10.3389/fgene.2013.00304

Abstract

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.

Highlights

High blood pressure (BP) is the leading cause of death in the United States, contributing to a wide spectrum of cardiovascular, cerebrovascular, and renal diseases (Chobanian et al, 2003)
Epidemiologic studies have shown that even modest control of BP on the range of 2–5 mmHg reduction can result in a significant decrease in cardiovascular disease mortality (Cook et al, 1995; Sacks et al, 2001; Whelton et al, 2002)
Since blood pressure-related traits are typically measured during ongoing drug therapy, consideration of single nucleotide polymorphisms (SNPs)-drug interactions may identify additional target loci associated with BP

Summary

Introduction

High blood pressure (BP) is the leading cause of death in the United States, contributing to a wide spectrum of cardiovascular, cerebrovascular, and renal diseases (Chobanian et al, 2003). Among US adults, the age-adjusted prevalence of HTN is 42.5% in African Americans (AA), 26.1% for Mexican Americans, and 29.1% for Non-Hispanic European Americans (EA). This disparity is greater for HTN than for other cardiovascular risk factors including dyslipidemia and diabetes (Fryar et al, 2010). Genetic studies of HTN and BP were largely limited to cohorts of European ancestry. It is still unknown the extent to which findings discovered in a European-based population are applicable to other race/ethnic groups (Rosenberg et al, 2010)

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