Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes

Pharmacogenomics J. 2018 Jan;18(1):106-112. doi: 10.1038/tpj.2016.67. Epub 2016 Sep 27.

Abstract

We conducted a discovery genome-wide association study with expression quantitative trait loci (eQTL) annotation of new-onset diabetes (NOD) among European Americans, who were exposed to a calcium channel blocker-based strategy (CCB strategy) or a β-blocker-based strategy (β-blocker strategy) in the INternational VErapamil SR Trandolapril STudy. Replication of the top signal from the SNP*treatment interaction analysis was attempted in Hispanic and African Americans, and a joint meta-analysis was performed (total 334 NOD cases and 806 matched controls). PLEKHH2 rs11124945 at 2p21 interacted with antihypertensive exposure for NOD (meta-analysis P=5.3 × 10-8). rs11124945 G allele carriers had lower odds for NOD when exposed to the β-blocker strategy compared with the CCB strategy (Odds ratio OR=0.38(0.24-0.60), P=4.0 × 10-5), whereas A/A homozygotes exposed to the β-blocker strategy had increased odds for NOD compared with the CCB strategy (OR=2.02(1.39-2.92), P=2.0 × 10-4). eQTL annotation of the 2p21 locus provides functional support for regulating gene expression.

Publication types

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

MeSH terms

  • Adrenergic beta-Antagonists / therapeutic use
  • African Americans
  • Aged
  • Alleles
  • Antihypertensive Agents / therapeutic use*
  • Calcium Channel Blockers / therapeutic use
  • Diabetes Mellitus / drug therapy*
  • Diabetes Mellitus / genetics*
  • Female
  • Follow-Up Studies
  • Genome-Wide Association Study / methods
  • Humans
  • Hypertension / drug therapy
  • Hypertension / genetics
  • Male
  • Meta-Analysis as Topic
  • Middle Aged
  • Odds Ratio
  • Pharmacogenetics / methods
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci / genetics*

Substances

  • Adrenergic beta-Antagonists
  • Antihypertensive Agents
  • Calcium Channel Blockers