Title | Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology. |
Publication Type | Publication |
Year | 2018 |
Authors | 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, 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 |
Journal | Pharmacogenomics J |
Volume | 18 |
Issue | 2 |
Pagination | 215-226 |
Date Published | 2018 Apr |
ISSN | 1473-1150 |
Keywords | Adult, Aged, Aged, 80 and over, aging, Cohort Studies, Electrocardiography, ethnicity, Female, Genomics, heart rate, Humans, Longitudinal Studies, Male, Middle Aged, Pharmacogenetics, Polymorphism, Single Nucleotide, Sodium Chloride Symporter Inhibitors |
Abstract | 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), we found suggestive evidence (P<5 × 10) 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. |
DOI | 10.1038/tpj.2017.10 |
Alternate Journal | Pharmacogenomics J |
PubMed ID | 28719597 |
PubMed Central ID | PMC5773415 |
Grant List | P30 ES010126 / ES / NIEHS NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States HHSN268201100012C / HL / NHLBI NIH HHS / United States UL1 RR033176 / RR / NCRR NIH HHS / United States R00 HL098458 / HL / NHLBI NIH HHS / United States R01 HL103612 / HL / NHLBI NIH HHS / United States HHSN268201100009I / HL / NHLBI NIH HHS / United States HHSN268201300005C / HL / NHLBI NIH HHS / United States HHSN268201100001I / HL / NHLBI NIH HHS / United States N01HC95160 / HL / NHLBI NIH HHS / United States N01 AG012100 / AG / NIA 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 N01 HC095167 / HC / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States N01HC95163 / HL / NHLBI NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States HHSN268201500001C / HL / NHLBI NIH HHS / United States HHSN268201100005G / HL / NHLBI NIH HHS / United States HHSN268201100004I / HL / NHLBI NIH HHS / United States HHSN268201100008I / 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 HHSN268201100007C / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States R01 HL085251 / HL / NHLBI NIH HHS / United States N01HC95169 / HL / NHLBI NIH HHS / United States HHSN268201100046C / HL / NHLBI NIH HHS / United States N01 HC025195 / HC / NHLBI NIH HHS / United States N01 HC095161 / HC / NHLBI NIH HHS / United States HHSN268201100011I / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States R01 HL086694 / HL / NHLBI NIH HHS / United States UL1 RR024156 / RR / NCRR NIH HHS / United States N02 HL64278 / HL / NHLBI NIH HHS / United States N01HC65236 / HL / NHLBI NIH HHS / United States N01 HC095164 / HC / NHLBI NIH HHS / United States HHSN268201300048C / HL / NHLBI NIH HHS / United States HHSN268201100003C / WH / WHI NIH HHS / United States N01HC65235 / HL / 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 N01HC95164 / HL / NHLBI 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 N01HC55222 / HL / NHLBI NIH HHS / United States N02HL64278 / HL / NHLBI NIH HHS / United States N01HC95162 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States N01HC65234 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States N01HC95168 / HL / NHLBI NIH HHS / United States R01 AG032098 / AG / NIA NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States T32 HL007779 / HL / NHLBI NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States N01HC65233 / HL / NHLBI NIH HHS / United States HHSN268201300049C / HL / NHLBI NIH HHS / United States N01HC65237 / HL / NHLBI NIH HHS / United States HHSN268201100005I / HL / NHLBI NIH HHS / United States N01 AG062103 / AG / NIA NIH HHS / United States HHSN271201100004C / AG / NIA NIH HHS / United States N01HC95165 / HL / NHLBI NIH HHS / United States N01 HC065236 / HC / NHLBI NIH HHS / United States HHSN268201500001I / HL / NHLBI NIH HHS / United States N01HC95161 / HL / NHLBI NIH HHS / United States HHSN268201300050C / HL / NHLBI NIH HHS / United States HHSN268201300047C / HL / NHLBI NIH HHS / United States HHSN268201100002C / WH / WHI NIH HHS / United States N01 HC095169 / HC / NHLBI NIH HHS / United States HHSN268200782096C / HL / NHLBI NIH HHS / United States N01 HC095165 / HC / NHLBI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States T32 CA009001 / CA / NCI NIH HHS / United States N01HC95167 / HL / NHLBI NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States N01 HC065235 / HC / NHLBI NIH HHS / United States N01 HC095168 / HC / NHLBI NIH HHS / United States HHSN268201100007I / HL / NHLBI NIH HHS / United States HHSN268201300046C / HL / NHLBI NIH HHS / United States HHSN268201100003I / HL / NHLBI NIH HHS / United States HHSN268201100002I / HL / NHLBI NIH HHS / United States N01 HC095163 / HC / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01HC95166 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States R01 HL087641 / HL / NHLBI NIH HHS / United States UL1 TR001881 / TR / NCATS NIH HHS / United States N01 HC095162 / HC / NHLBI NIH HHS / United States U01 HG005152 / HG / NHGRI NIH HHS / United States T32 HL007055 / HL / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States HHSN268201100001C / WH / WHI NIH HHS / United States U54 GM115428 / GM / NIGMS NIH HHS / United States HHSN271201200022C / DA / NIDA NIH HHS / United States HHSN268201100004C / WH / WHI 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 N01HC85081 / HL / NHLBI NIH HHS / United States |
Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.
MS#:
0395
ECI:
Yes
Manuscript Affiliation:
Coordinating Center - Collaborative Studies Coordinating Center - UNC at Chapel Hill
Manuscript Status:
Published