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

TitlePharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.
Publication TypeJournal Article
Year of Publication2017
AuthorsSeyerle, 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, DI Chen, Y-, 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
JournalPharmacogenomics J
Date Published2017 Jul 18
ISSN1473-1150
Abstract<p>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.</p>
DOI10.1038/tpj.2017.10
Alternate JournalPharmacogenomics J.
PubMed ID28719597
Grant ListUL1 RR033176 / RR / NCRR NIH HHS / United States
R00 HL098458 / HL / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
N01 AG062101 / AG / NIA NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
R01 ES017794 / ES / NIEHS NIH HHS / United States
R01 HL085251 / HL / NHLBI NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
N01 HC095161 / HC / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
UL1 RR024156 / RR / NCRR NIH HHS / United States
N01 HC095164 / HC / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
N01 HC095166 / HC / NHLBI NIH HHS / United States
N01 HC065237 / HC / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01 AG062106 / AG / NIA NIH HHS / United States
N01 HC095160 / HC / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 AG032098 / AG / NIA NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
T32 HL007779 / HL / NHLBI NIH HHS / United States
N01 HC065236 / HC / NHLBI NIH HHS / United States
N01 HC095165 / HC / NHLBI NIH HHS / United States
N01 HC065235 / HC / NHLBI NIH HHS / United States
N01 HC095163 / HC / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
U01 HG005152 / HG / NHGRI NIH HHS / United States
T32 HL007055 / HL / NHLBI NIH HHS / United States
K23 HL080025 / HL / NHLBI NIH HHS / United States
R01 HL111089 / HL / NHLBI NIH HHS / United States
R01 HL116747 / HL / NHLBI NIH HHS / United States
N01 HC095159 / HC / NHLBI NIH HHS / United States
ePub date: 
17/07