Pharmacogenomics of hypertension: a genome‐wide, placebo‐controlled cross‐over study, using four classes of antihypertensive drugs

Abstract

Background: Identification of genetic markers of antihypertensive drug responses could assist in individualization of hypertension treatment.

Methods and results: We conducted a genome-wide association study to identify gene loci influencing the responsiveness of 228 male patients to 4 classes of antihypertensive drugs. The Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study is a double-blind, placebo-controlled cross-over study where each subject received amlodipine, bisoprolol,hydrochlorothiazide, and losartan, each as a monotherapy, in a randomized order. Replication analyses were performed in 4 studies with patients of European ancestry (PEAR Study, N=386; GERA I and II Studies, N=196 and N=198; SOPHIA Study, N=372). We identified 3 single-nucleotide polymorphisms within the ACY3 gene that showed associations with bisoprolol response reaching genome-wide significance (P<5x10(-8))however, this could not be replicated in the PEAR Study using atenolol. In addition, 39 single-nucleotide polymorphisms showed P values of 10(-5) to 10(-7). The 20 top-associated single-nucleotide polymorphisms were different for each antihypertensive drug. None of these top single-nucleotide polymorphisms co-localized with the panel of >40 genes identified in genome-wide association studies of hypertension. Replication analyses of GENRES results provided suggestive evidence for a missense variant (rs3814995) in the NPHS1 (nephrin) gene influencing losartan response, and for 2 variants influencing hydrochlorothiazide response, located within or close to the ALDH1A3 (rs3825926) and CLIC5 (rs321329) genes.

Conclusions: These data provide some evidence for a link between biology of the glomerular protein nephrin and antihypertensive action of angiotensin receptor antagonists and encourage additional studies on aldehyde dehydrogenase–mediated reactions in antihypertensive drug action.

Figure 1.

Manhattan plots from the genome‐wide association analysis of the ambulatory blood pressure responses using an additive model. (A) Losartan, systolic; (B) losartan, diastolic; (C) bisoprolol, systolic; (D) bisoprolol, diastolic; (E) amlodipine, systolic; (F) amlodipine, diastolic; (G) hydrochlorothiazide, systolic; (H) hydrochlorothiazide, diastolic.

Figure 2.

Quantile‐quantile plots from the genome‐wide association analysis of the ambulatory blood pressure responses using an additive model. Single‐nucleotide polymorphisms with minor allele frequency <0.01 are excluded. (A) Losartan, systolic; (B) losartan, diastolic; (C) bisoprolol, systolic; (D) bisoprolol, diastolic; (E) amlodipine, systolic; (F) amlodipine, diastolic; (G) hydrochlorothiazide, systolic; (H) hydrochlorothiazide, diastolic.