Abstract 2074: Association of Hypertension Drug Target Genes With Blood Pressure and Hypertension: Results From a Genome-wide Association Study in 29,136 Individuals
Blood pressure (BP) reduction in hypertensive individuals reduces the risk of cardiovascular complications. To achieve BP control patients often require multiple medications, and trial and error switching of drug classes, indicating inter-individual differences attributable to many factors, including genetic effects. A recent genome-wide association study (GWAS) and meta-analyses of systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 29,136 individuals from 6 population-based cohorts of European ancestry identified and replicated multiple genome-wide significant novel BP loci. We hypothesized based on physiology that associations of antihypertensive drug target genes within this GWAS could suggest associations with BP. We identified 31 genes whose corresponding proteins are targets of anti-hypertensives, including receptors targeted within the renin-angiotensin system, and by diuretics, adrenoceptor blockers and calcium channel blockers. We examined associations for SBP, DBP, and HTN to 31 anti-hypertensive drug target gene regions, including all SNPs tested in the GWAS within these genes and 60 kb flanking regions around them. We compared the strongest association in each gene region to the most significant associations in random re-samplings (n=1,000) of identical numbers of consecutive SNPs within the same GWAS results datasets. Allowing for multiple comparisons this method identified evidence of association of ADRB1, ADRB2, AGT, CACNA1A, CACNA1C, and SLC12A3 polymorphisms with one or more BP traits. An intronic SNP (rs1985579, G>A) in CACNA1A had the lowest GWAS p value among SNPs tested; the minor allele was associated with low SBP (p=2.6×10−5), DBP (p=1.5×10−4) and odds of HTN (p=2.9×10−3). In the ADRB1 region, the Arg389Gly polymorphism (rs1801253, C>G) showed the strongest association with the Gly allele associated with decreased SBP (p=7.3×10−4) and DBP (p=7.5×10−4), a finding that is consistent with prior studies.
Conclusions: Our results suggest that further studies of these genes in relation to BP and potential pharmacogenetic interactions may be warranted. CACNA1A, previously implicated in genetic susceptibility to migraines, potentially represents a novel BP candidate gene.