Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.
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.
Seyerle, AA; Sitlani, CM; Noordam, R; Gogarten, SM; Li, J; Li, X; Evans, DS; Sun, F; Laaksonen, MA; Isaacs, A; Kristiansson, K; Highland, HM; Stewart, JD; Harris, TB; Trompet, S; Bis, JC; Peloso, GM; Brody, JA; Broer, L; Busch, EL; Duan, Q; Stilp, AM; O'Donnell, CJ; Macfarlane, PW; Floyd, JS; Kors, JA; Lin, HJ; Li-Gao, R; Sofer, T; Méndez-Giráldez, R; Cummings, SR; Heckbert, SR; Hofman, A; Ford, I; Li, Y; Launer, LJ; Porthan, K; Newton-Cheh, C; Napier, MD; Kerr, KF; Reiner, AP; Rice, KM; Roach, J; Buckley, BM; Soliman, EZ; de Mutsert, R; Sotoodehnia, N; Uitterlinden, AG; North, KE; Lee, CR; Gudnason, V; Stürmer, T; Rosendaal, FR; Taylor, KD; Wiggins, KL; Wilson, JG; Chen, Y-D; Kaplan, RC; Wilhelmsen, K; Cupples, LA; Salomaa, V; van Duijn, C; Jukema, JW; Liu, Y; Mook-Kanamori, DO; Lange, LA; Vasan, RS; Smith, AV; Stricker, BH; Laurie, CC; Rotter, JI; Whitsel, EA; Psaty, BM; Avery, CL
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