Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology

Pharmacogenomics J. 2018 Apr;18(2):215-226. doi: 10.1038/tpj.2017.10. Epub 2017 Jul 18.

Abstract

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / drug effects
  • Aging / ethnology
  • Aging / genetics*
  • Cohort Studies
  • Electrocardiography / drug effects
  • Electrocardiography / trends
  • Ethnic Groups / genetics*
  • Female
  • Genomics / methods
  • Genomics / trends*
  • Heart Rate / drug effects
  • Heart Rate / genetics*
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Pharmacogenetics / methods
  • Pharmacogenetics / trends*
  • Polymorphism, Single Nucleotide / drug effects
  • Polymorphism, Single Nucleotide / genetics
  • Sodium Chloride Symporter Inhibitors / pharmacology*

Substances

  • Sodium Chloride Symporter Inhibitors

Grant support