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

Timo P. Hiltunen, Kati M. Donner, Antti Pekka Sarin, Janna Saarela, Samuli Ripatti, Arlene B. Chapman, John G. Gums, Yan Gong, Rhonda M. Cooper-DeHoff, Francesca Frau, Valeria Glorioso, Roberta Zaninello, Erika Salvi, Nicola Glorioso, Eric Boerwinkle, Stephen T Turner, Julie A. Johnson, Kimmo K. Kontula

Research output: Contribution to journalArticle

37 Scopus citations

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<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.

Original languageEnglish (US)
Article numbere001521
JournalJournal of the American Heart Association
Volume4
Issue number1
DOIs
StatePublished - Jan 1 2015

    Fingerprint

Keywords

  • Antihypertensive drug
  • Association study
  • Drug response
  • Genome-wide
  • Hypertension

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Hiltunen, T. P., Donner, K. M., Sarin, A. P., Saarela, J., Ripatti, S., Chapman, A. B., Gums, J. G., Gong, Y., Cooper-DeHoff, R. M., Frau, F., Glorioso, V., Zaninello, R., Salvi, E., Glorioso, N., Boerwinkle, E., Turner, S. T., Johnson, J. A., & Kontula, K. K. (2015). Pharmacogenomics of hypertension: A genome-wide, placebo-controlled cross-over study, using four classes of antihypertensive drugs. Journal of the American Heart Association, 4(1), [e001521]. https://doi.org/10.1161/JAHA.114.001521