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Pharmacogenomics Study of Thiazide Diuretics and QT Interval in Multi-Ethnic Populations: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)

Amanda A. Seyerle,C. Sitlani,R. Noordam,S. Gogarten,Jin Li,Xiaohui Li,Daniel S. Evans,F. Sun,M. Laaksonen,A. Isaacs,K. Kristiansson,H. Highland,J. Stewart,T. Harris,S. Trompet,J. Bis,G. Peloso,J. Brody,L. Broer,E. Busch,Qing Duan,A. Stilp,C. O’Donnell,P. Macfarlane,J. Floyd,J. Kors,Henry J. Lin,R. Li-Gao,T. Sofer,R. Méndez-Giráldez,S. Cummings,S. Heckbert,A. Hofman,I. Ford,Yun Li,L. Launer,K. Porthan,C. Newton‐Cheh,Melanie D. Napier,Kathleen F. Kerr,A. Reiner,K. Rice,J. Roach,B. Buckley,E. Soliman,R. de Mutsert,N. Sotoodehnia,A. Uitterlinden,K. North,Craig R. Lee,V. Gudnason,T. Stürmer,F. Rosendaal,K. Taylor,K. Wiggins,James G. Wilson,Y. Chen,R. Kaplan,K. Wilhelmsen,L. Cupples,V. Salomaa,C. V. van Duijn,J. Jukema,Yongmei Liu,D. Mook-Kanamori,L. Lange,R. Vasan,A. Smith,B. Stricker,C. Laurie,J. Rotter,E. Whitsel,B. Psaty,C. Avery

Published 2017 in The Pharmacogenomics Journal

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.

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