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

A. A. Seyerle*, C. M. Sitlani, R. Noordam, S. M. Gogarten, J. Li, X. Li, D. S. Evans, F. Sun, M. A. Laaksonen, A. Isaacs, K. Kristiansson, H. M. Highland, J. D. Stewart, T. B. Harris, S. Trompet, J. C. Bis, G. M. Peloso, J. A. Brody, L. Broer, E. L. BuschQ. Duan, A. M. Stilp, C. J. O'Donnell, P. W. Macfarlane, J. S. Floyd, J. A. Kors, H. J. Lin, R. Li-Gao, T. Sofer, R. Mendez-Giraldez, S. R. Cummings, S. R. Heckbert, A. Hofman, I Ford, Y. Li, L. J. Launer, K. Porthan, C. Newton-Cheh, M. D. Napier, K. F. Kerr, A. P. Reiner, K. M. Rice, J. Roach, B. M. Buckley, E. Z. Soliman, R. de Mutsert, N. Sotoodehnia, A. G. Uitterlinden, K. E. North, C. R. Lee, V Gudnason, T. Sturmer, F. R. Rosendaal, K. D. Taylor, K. L. Wiggins, J. G. Wilson, Y-D Chen, R. C. Kaplan, K. Wilhelmsen, L. A. Cupples, V Salomaa, C. van Duijn, J. W. Jukema, Y. Liu, D. O. Mook-Kanamori, L. A. Lange, R. S. Vasan, A. Smith, B. H. Stricker, C. C. Laurie, J. Rotter, E. A. Whitsel, B. M. Psaty, C. L. Avery

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Web of Science)

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, transethnic 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 x 10(-8)), we found suggestive evidence (P < 5 x 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.
Original languageEnglish
Pages (from-to)215-226
Number of pages12
JournalPharmacogenomics Journal
Volume18
Issue number2
DOIs
Publication statusPublished - 1 Mar 2018

Keywords

  • BLOOD-PRESSURE RESPONSE
  • INFLUENCING ANTIHYPERTENSIVE RESPONSE
  • GENE-ENVIRONMENT INTERACTIONS
  • WIDE ASSOCIATION
  • GENOMEWIDE ASSOCIATION
  • HYPERTENSIVE PATIENTS
  • CARDIOVASCULAR DRUGS
  • SELECTION BIAS
  • UNITED-STATES
  • VARIANTS

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