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

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<5×10-8); 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. © 2015 the authors.