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

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

Published In Pharmacogenomics J, (2018 Apr)

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.

PubMed ID: 28719597

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