OP.7C.10] IDENTIFICATION OF GENE VARIANTS ASSOCIATED WITH ANTIHYPERTENSIVE RESPONSES TO BETA BLOCKERS AND LOSARTAN

Abstract

Objective: A genome-wide association study on Genetics of Drug Responsiveness in Essential Hypertension (GENRES) identified four single nucleotide polymorphisms (SNPs) associated with blood pressure (BP) response to bisoprolol and three SNPs associated with BP response to losartan in Finnish men. Here we replicate these results using the Finnish subjects of the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE). Design and method: The LIFE study subcohort included 927 men and women with hypertension that were randomized to atenolol (N = 467) or losartan (N = 460) based treatment. We analysed the BP response at the two months’ visit when the subjects were using a monotherapy with 50 mg of atenolol or 50 mg of losartan, or a combination therapy with 12.5 mg of hydrochlorothiazide added to the monotherapy (approximately half of the subjects). The DNA samples were genotyped using Illumina HumanOmniExpress-12 BeadChip. We used an additive genetic model and linear regression with appropriate covariates to analyze the associations of the four bisoprolol-associated SNPs (GENRES) with BP responses to atenolol-based treatment (LIFE), and the three losartan-associated GENRES SNPs with BP responses to losartan in LIFE. Separate analysis was performed in men if SNP*sex interaction was significant (P < 0.05). Results: rs2514036 on chromosome 11 within the ACY3 gene was associated with systolic (beta = -5.5 mmHg, P = 0.005) and diastolic (beta = -1.9 mmHg, P = 0.05) BP responses to atenolol in men. The effect was in the same direction as the effect on bisoprolol response in GENRES. rs3814995 on chromosome 19 in the NPHS1 gene was associated with diastolic BP response to losartan (beta = -0.9 mmHg, P = 0.04), again with the same direction of effect. Conclusions: This replication study supports earlier findings that rs2514036 within the ACY3 gene is associated with BP response to beta blockers and that rs3814995 in NPHS1 gene coding for nephrin is associated with BP response to losartan. The findings suggest these SNPs could be used as genetic markers for selecting optimal antihypertensive therapy. The findings also encourage further research on the role of ACY3 and NPHS1 genes in the antihypertensive effect of beta blockers and losartan, respectively.