TY - JOUR T1 - Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology. JF - Pharmacogenomics J Y1 - 2017 A1 - Seyerle, A A A1 - Sitlani, C M A1 - Noordam, R A1 - Gogarten, S M A1 - Li, J A1 - Li, X A1 - Evans, D S A1 - Sun, F A1 - Laaksonen, M A A1 - Isaacs, A A1 - Kristiansson, K A1 - Highland, H M A1 - Stewart, J D A1 - Harris, T B A1 - Trompet, S A1 - Bis, J C A1 - Peloso, G M A1 - Brody, J A A1 - Broer, L A1 - Busch, E L A1 - Duan, Q A1 - Stilp, A M A1 - O'Donnell, C J A1 - Macfarlane, P W A1 - Floyd, J S A1 - Kors, J A A1 - Lin, H J A1 - Li-Gao, R A1 - Sofer, T A1 - Méndez-Giráldez, R A1 - Cummings, S R A1 - Heckbert, S R A1 - Hofman, A A1 - Ford, I A1 - Li, Y A1 - Launer, L J A1 - Porthan, K A1 - Newton-Cheh, C A1 - Napier, M D A1 - Kerr, K F A1 - Reiner, A P A1 - Rice, K M A1 - Roach, J A1 - Buckley, B M A1 - Soliman, E Z A1 - de Mutsert, R A1 - Sotoodehnia, N A1 - Uitterlinden, A G A1 - North, K E A1 - Lee, C R A1 - Gudnason, V A1 - Stürmer, T A1 - Rosendaal, F R A1 - Taylor, K D A1 - Wiggins, K L A1 - Wilson, J G A1 - Chen, Y-DI A1 - Kaplan, R C A1 - Wilhelmsen, K A1 - Cupples, L A A1 - Salomaa, V A1 - van Duijn, C A1 - Jukema, J W A1 - Liu, Y A1 - Mook-Kanamori, D O A1 - Lange, L A A1 - Vasan, R S A1 - Smith, A V A1 - Stricker, B H A1 - Laurie, C C A1 - Rotter, J I A1 - Whitsel, E A A1 - Psaty, B M A1 - Avery, C L AB -

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.The Pharmacogenomics Journal advance online publication, 18 July 2017; doi:10.1038/tpj.2017.10.

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