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Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

TitleLarge-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.
Publication TypePublication
Year2018
AuthorsFloyd JS, Sitlani CM, Avery CL, Noordam R, Li X, Smith AV, Gogarten SM, Li J, Broer L, Evans DS, Trompet S, Brody JA, Stewart JD, Eicher JD, Seyerle AA, Roach J, Lange LA, Lin HJ, Kors JA, Harris TB, Li-Gao R, Sattar N, Cummings SR, Wiggins KL, Napier MD, Stürmer T, Bis JC, Kerr KF, Uitterlinden AG, Taylor KD, Stott DJ, de Mutsert R, Launer LJ, Busch EL, Méndez-Giráldez R, Sotoodehnia N, Soliman EZ, Li Y, Duan Q, Rosendaal FR, Slagboom PE, Wilhelmsen KC, Reiner AP, Di Chen Y-, Heckbert SR, Kaplan RC, Rice KM, Jukema JW, Johnson AD, Liu Y, Mook-Kanamori DO, Gudnason V, Wilson JG, Rotter JI, Laurie CC, Psaty BM, Whitsel EA, Cupples LA, Stricker BH
JournalPharmacogenomics J
Volume18
Issue1
Pagination127-135
Date Published2018 01
ISSN1473-1150
KeywordsAged, Cardiovascular Diseases, Cytochrome P-450 CYP2C9, Diabetes Mellitus, Type 2, Drug-Related Side Effects and Adverse Reactions, Electrocardiography, ethnic groups, Female, Genetic Variation, genome-wide association study, Humans, Male, Middle Aged, Pharmacogenetics, Pharmacogenomic Testing, Sulfonylurea Compounds
Abstract

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

DOI10.1038/tpj.2016.90
Alternate JournalPharmacogenomics J
PubMed ID27958378
PubMed Central IDPMC5468495
Grant ListHHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1 RR033176 / RR / NCRR 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
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UL1 RR025005 / RR / NCRR NIH HHS / United States
N01 AG062101 / AG / NIA 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
HHSN268201100005G / HL / NHLBI NIH HHS / United States
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MS#: 
0396
Manuscript Lead/Corresponding Author Affiliation: 
HCHS/SOL Genetic Analysis Center - University of Washington, Seattle
ECI: 
Yes
Manuscript Affiliation: 
HCHS/SOL Genetic Analysis Center - University of Washington, Seattle
Manuscript Status: 
Published