03872nas a2200997 4500008004100000022001400041245016000055210006900215260001600284520133100300100001801631700001801649700001501667700001901682700001001701700001001711700001601721700001101737700002001748700001401768700002001782700001901802700001801821700001601839700001501855700001301870700001701883700001601900700001301916700001601929700001201945700001601957700001901973700002101992700001602013700001502029700001402044700001402058700001302072700002502085700001902110700001802129700001402147700001202161700001002173700001602183700001502199700001902214700001702233700001502250700001702265700001502282700001302297700001802310700001802328700001802346700001902364700002202383700001602405700001402421700001602435700001602451700002002467700001702487700001802504700001702522700001602539700001702555700001802572700001802590700001502608700001702623700001702640700001102657700002402668700001602692700001502708700001502723700001802738700001702756700001602773700001802789700001502807700001602822856003602838 2017 eng d a1473-115000aPharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.0 aPharmacogenomics study of thiazide diuretics and QT interval in c2017 Jul 183 a
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.
1 aSeyerle, A, A1 aSitlani, C, M1 aNoordam, R1 aGogarten, S, M1 aLi, J1 aLi, X1 aEvans, D, S1 aSun, F1 aLaaksonen, M, A1 aIsaacs, A1 aKristiansson, K1 aHighland, H, M1 aStewart, J, D1 aHarris, T B1 aTrompet, S1 aBis, J C1 aPeloso, G, M1 aBrody, J, A1 aBroer, L1 aBusch, E, L1 aDuan, Q1 aStilp, A, M1 aO'Donnell, C J1 aMacfarlane, P, W1 aFloyd, J, S1 aKors, J, A1 aLin, H, J1 aLi-Gao, R1 aSofer, T1 aMéndez-Giráldez, R1 aCummings, S, R1 aHeckbert, S R1 aHofman, A1 aFord, I1 aLi, Y1 aLauner, L J1 aPorthan, K1 aNewton-Cheh, C1 aNapier, M, D1 aKerr, K, F1 aReiner, A, P1 aRice, K, M1 aRoach, J1 aBuckley, B, M1 aSoliman, E, Z1 ade Mutsert, R1 aSotoodehnia, N1 aUitterlinden, A G1 aNorth, K, E1 aLee, C, R1 aGudnason, V1 aStürmer, T1 aRosendaal, F, R1 aTaylor, K, D1 aWiggins, K, L1 aWilson, J, G1 aDI Chen, Y-1 aKaplan, R, C1 aWilhelmsen, K1 aCupples, L, A1 aSalomaa, V1 avan Duijn, C1 aJukema, J, W1 aLiu, Y1 aMook-Kanamori, D, O1 aLange, L, A1 aVasan, R S1 aSmith, A V1 aStricker, B H1 aLaurie, C, C1 aRotter, J I1 aWhitsel, E, A1 aPsaty, B M1 aAvery, C, L uhttps://chs-nhlbi.org/node/7491