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

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.

%B Pharmacogenomics J %8 2017 Jul 18 %G eng %R 10.1038/tpj.2017.10