Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses)

Caitrin W McDonough, Oyunbileg Magvanjav, Ana C C Sá, Nihal M El Rouby, Chintan Dave, Amelia N Deitchman, Marina Kawaguchi-Suzuki, Wenbin Mei, Yong Shen, Ravi Shankar Prasad Singh, Mohamed Solayman, Kent R Bailey, Eric Boerwinkle, Arlene B Chapman, John G Gums, Amy Webb, Steven E Scherer, Wolfgang Sadee, Stephen T Turner, Rhonda M Cooper-DeHoff, Yan Gong, Julie A Johnson

Plasma renin is an important regulator of blood pressure (BP). Plasma renin activity (PRA) has been shown to correlate with variability in BP response to antihypertensive agents. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with baseline PRA using data from the PEAR study (Pharmacogenomic Evaluation of Antihypertensive Responses). Multiple linear regression analysis was performed in 461 whites and 297 blacks using an additive model, adjusting for age, sex, and ancestry-specific principal components. Top SNPs were prioritized by testing the expected direction of association for BP response to atenolol and hydrochlorothiazide. Top regions from the BP response prioritization were tested for functional evidence through differences in gene expression by genotype using RNA sequencing data. Regions with functional evidence were assessed for replication with baseline PRA in an independent study (PEAR-2). Our top SNP rs3784921 was in the SNN-TXNDC11 gene region. The G allele of rs3784921 was associated with higher baseline PRA (β=0.47; P=2.09×10-6) and smaller systolic BP reduction in response to hydrochlorothiazide (β=2.97; 1-sided P=0.006). In addition, TXNDC11 expression differed by rs3784921 genotype (P=0.007), and rs1802409, a proxy SNP for rs3784921 (r2=0.98-1.00), replicated in PEAR-2 (β=0.15; 1-sided P=0.038). Additional SNPs associated with baseline PRA that passed BP response prioritization were in/near the genes CHD9, XIRP2, and GHR. CONCLUSIONS: We identified multiple regions associated with baseline PRA that were prioritized through BP response signals to 2 mechanistically different antihypertensive drugs. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.