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

dc.contributor.authorSeyerle, A. A.
dc.contributor.authorSitlani, C. M.
dc.contributor.authorNoordam, R.
dc.contributor.authorGogarten, S. M.
dc.contributor.authorLi, J.
dc.contributor.authorLi, X.
dc.contributor.authorEvans, Daniel S.
dc.contributor.authorSun, F.
dc.contributor.authorLaaksonen, M. A.
dc.contributor.authorIsaacs, A.
dc.contributor.authorKristiansson, K.
dc.contributor.authorHighland, H. M.
dc.contributor.authorStewart, J. D.
dc.contributor.authorHarris, T. B.
dc.contributor.authorTrompet, S.
dc.contributor.authorBis, Joshua C.
dc.contributor.authorPeloso, G. M.
dc.contributor.authorBrody, Jennifer A.
dc.contributor.authorBroer, L.
dc.contributor.authorBusch, E. L.
dc.contributor.authorDuan, Q.
dc.contributor.authorStilp, A. M.
dc.contributor.authorO'Donnell, C. J.
dc.contributor.authorMacfarlane, P. W.
dc.contributor.authorFloyd, J. S.
dc.contributor.authorKors, J. A.
dc.contributor.authorLin, H. J.
dc.contributor.authorLi-Gao, R.
dc.contributor.authorSofer, T.
dc.contributor.authorMendez-Giraldez, R.
dc.contributor.authorCummings, S. R.
dc.contributor.authorHeckbert, S. R.
dc.contributor.authorHofman, A.
dc.contributor.authorFord, Ian
dc.contributor.authorLi, Y.
dc.contributor.authorLauner, L. J.
dc.contributor.authorPorthan, K.
dc.contributor.authorNewton-Cheh, C.
dc.contributor.authorNapier, M. D.
dc.contributor.authorKerr, K. F.
dc.contributor.authorReiner, A. P.
dc.contributor.authorRice, K. M.
dc.contributor.authorRoach, J.
dc.contributor.authorBuckley, Brendan M.
dc.contributor.authorSoliman, E. Z.
dc.contributor.authorde Mutsert, R.
dc.contributor.authorSotoodehnia, Nona
dc.contributor.authorUitterlinden, A. G.
dc.contributor.authorNorth, K. E.
dc.contributor.authorLee, C. R.
dc.contributor.authorGudnason, V
dc.contributor.authorSturmer, T.
dc.contributor.authorRosendaal, F. R.
dc.contributor.authorTaylor, K. D.
dc.contributor.authorWiggins, K. L.
dc.contributor.authorWilson, J. G.
dc.contributor.authorChen, Y-D, I
dc.contributor.authorKaplan, R. C.
dc.contributor.authorWilhelmsen, K.
dc.contributor.authorCupples, L. A.
dc.contributor.authorSalomaa, V
dc.contributor.authorvan Duijn, C.
dc.contributor.authorJukema, J. W.
dc.contributor.authorLiu, Y.
dc.contributor.authorMook-Kanamori, D. O.
dc.contributor.authorLange, L. A.
dc.contributor.authorVasan, R. S.
dc.contributor.authorSmith, A., V
dc.contributor.authorStricker, B. H.
dc.contributor.authorLaurie, C. C.
dc.contributor.authorRotter, J., I
dc.contributor.authorWhitsel, E. A.
dc.contributor.authorPsaty, B. M.
dc.contributor.authorAvery, Christy L.
dc.contributor.funderFifth Framework Programme
dc.contributor.funderSixth Framework Programme
dc.contributor.funderSeventh Framework Programme
dc.description.abstractThiazide 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, transethnic 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 x 10(-8)), we found suggestive evidence (P < 5 x 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.en
dc.description.sponsorshipFifth Framework Programme (Grant Number QLG2-CT-2002-01254)' NIH (N01-AG-1-2100, 271201200022C, HL080025); NIA Intramural Research Program; Hjartavernd (Icelandic Heart Association); Althingi (Icelandic Parliament); National Heart, Lung and Blood Institute (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694, R01-HL-103612, R00-HL-098458); National Human Genome Research Institute (U01HG004402); National Institutes of Health (HHSN268200625226C, HHSN268200782096C); National Institutes of Health; NIH Roadmap for Medical Research; NHLBI Training grants (T32HL7055, T32HL07779); NHLBI (HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, HL130114, R01HL085251, HSN 26220/20054C); National Institute on Aging (NIA) (R01AG023629); National Center for Advancing Translational Sciences, CTSI grant (UL1TR000124); National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant (DK063491); European Commission FP6 STRP (018947 (LSHG-CT-2006-01947)); European Community's Seventh Framework Programme (FP7) by the European Commission under the programme 'Quality of Life and Management of the Living Resources' of 5th Framework Programme (HEALTH-F4-2007-201413, QLG2-CT-2002-01254); ENGAGE consortium; CMSB; Netherlands Organisation for Scientific Research; Russian Foundation for Basic Research (NWO-RFBR 047.017.043); ZonMw grant (91111025); National Heart Lung and Blood Institute of the National Institutes of Health; Boston University School of Medicine (N01-HC-25195, HHSN268201500001I); Affymetrix for genotyping services (N02-HL-6-4278); Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; Doris Duke Charitable Foundation; Burroughs Wellcome Fund; Orion-Farmos Research Foundation; Finnish Foundation for Cardiovascular Research; Academy of Finland (129494, 139635); NIA (N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1); Intramural Research Program of the NIH, National Institute on Aging; National Heart, Lung, and Blood Institute (NHLBI) (N01-HC65233); University of Miami (N01-HC65234); Albert Einstein College of Medicine (N01-HC65235); Northwestern University (N01-HC65236); San Diego State University (N01-HC65237); NHLBI; NIDCR (HHSN268201300005C AM03, MOD03); NCATS CTSI grant (UL1TR000124); NIDDK Diabetes Research Center (DRC) (DK063491); National Heart, Lung, and Blood Institute (HHSN268201300046C, HHSN268201300047C, HSN268201300048C, HHSN268201300049C, HHSN268201300050C); National Institute on Minority Health and Health Disparities; National Heart, Lung and Blood Institute (NHLBI); Clinical Translational Science Institute grant (UL1RR033176); Centre National de Genotypage (Paris, France); Leiden University Medical Center; Leiden University, Research Profile Area Vascular and Regenerative Medicine; Dutch Science Organization (ZonMW-VENI Grant) (916.14.023); Bristol-Myers Squibb; Netherlands Heart Foundation (2001 D 032); seventh framework program of the European commission (223004); Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) (050-060-810); Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly; Netherlands Heart Foundation; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911.03.012); Research Institute for Diseases in the Elderly (RIDE); Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Project (050-060-810); National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C); National Cancer Institute (5T32CA009001); National Human Genome Research Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01HG005152); National Institute of Environmental Health Sciences, National Institutes of Health, U. S. Department of Health and Human Services (R01ES017794); National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services (HHSN268201100046C, N02HL64278); (UL1RR025005); (R01HL116747); (RO1HL111089); (N01-HC-95159); (N01-HC-95160); (N01-HC-95161); (N01-HC-95162); (N01-HC-95163); (N01-HC-95164); (N01-HC-95165); (N01-HC-95166); (N01-HC-95167); (N01-HC-95168); (N01-HC-95169); (RR-024156)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.identifier.citationSeyerle, A. A., et al. (2017) ‘Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology’, Pharmacogenomics Journal, 18, pp. 215-226. doi. 10.1038/tpj.2017.10en
dc.identifier.journaltitlePharmacogenomics Journalen
dc.publisherNature Publishing Groupen
dc.relation.projectinfo:eu-repo/grantAgreement/NIH/NATIONAL INSTITUTE ON AGING/5U01AG018947-07/US/Multicenter Osteoarthritis Study (MOST)/
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::HEALTH/201413/EU/European Network for Genetic and Genomic Epidemiology/ENGAGE
dc.rights© 2017, Nature Publishing Group. All rights reserved. This is the peer reviewed version of the following article: Seyerle, A. A. et al. (2017) ‘Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology’, The Pharmacogenomics Journal, 18, pp. 215-226. doi. 10.1038/tpj.2017.10, which has been published in final form at
dc.subjectBlood-pressure responseen
dc.subjectInfluencing antihypertensive responseen
dc.subjectGene-environment interactionsen
dc.subjectWide associationen
dc.subjectGenomewide associationen
dc.subjectHypertensive patientsen
dc.subjectCardiovascular drugsen
dc.subjectSelection biasen
dc.subjectUnited Statesen
dc.titlePharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiologyen
dc.typeArticle (peer-reviewed)en
Original bundle
Now showing 1 - 2 of 2
Thumbnail Image
Pharmacogenomics Study of Thiazide Diuretics and QT Interval-1.docx
2.05 MB
Microsoft Word XML
Supplemental File 1
Thumbnail Image
767.2 KB
Adobe Portable Document Format
Accepted Version