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

J Am Heart Assoc. 2015 Jan 26;4(1):e001521. doi: 10.1161/JAHA.115.001778.

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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aldehyde Oxidoreductases / genetics
  • Amlodipine / therapeutic use
  • Antihypertensive Agents / pharmacology
  • Antihypertensive Agents / therapeutic use*
  • Benzimidazoles / therapeutic use
  • Bisoprolol / therapeutic use
  • Blood Pressure Monitoring, Ambulatory
  • Chloride Channels / genetics
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Essential Hypertension
  • Finland
  • Genome-Wide Association Study
  • Humans
  • Hydrochlorothiazide / therapeutic use
  • Hypertension / diagnosis
  • Hypertension / drug therapy*
  • Hypertension / genetics*
  • Losartan / therapeutic use
  • Male
  • Membrane Proteins / genetics*
  • Meta-Analysis as Topic
  • Microfilament Proteins / genetics
  • Middle Aged
  • Mutation, Missense
  • Pharmacogenetics / methods*
  • Polymorphism, Single Nucleotide
  • Severity of Illness Index
  • Tetrazoles / therapeutic use
  • Treatment Outcome

Substances

  • Antihypertensive Agents
  • Benzimidazoles
  • CLIC5 protein, human
  • Chloride Channels
  • Membrane Proteins
  • Microfilament Proteins
  • Tetrazoles
  • nephrin
  • Hydrochlorothiazide
  • Amlodipine
  • Aldehyde Oxidoreductases
  • aldehyde dehydrogenase (NAD(P)+)
  • Losartan
  • candesartan
  • Bisoprolol