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

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 × 10-8), 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.

SUBMITTER: Floyd JS

PROVIDER: S-EPMC5468495 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Floyd J S JS Sitlani C M CM Avery C L CL Noordam R R Li X X Smith A V AV Gogarten S M SM Li J J Broer L L Evans D S DS Trompet S S Brody J A JA Stewart J D JD Eicher J D JD Seyerle A A AA Roach J J Lange L A LA Lin H J HJ Kors J A JA Harris T B TB Li-Gao R R Sattar N N Cummings S R SR Wiggins K L KL Napier M D MD Stürmer T T Bis J C JC Kerr K F KF Uitterlinden A G AG Taylor K D KD Stott D J DJ de Mutsert R R Launer L J LJ Busch E L EL Méndez-Giráldez R R Sotoodehnia N N Soliman E Z EZ Li Y Y Duan Q Q Rosendaal F R FR Slagboom P E PE Wilhelmsen K C KC Reiner A P AP Chen Y-Di YD Heckbert S R SR Kaplan R C RC Rice K M KM Jukema J W JW Johnson A D AD Liu Y Y Mook-Kanamori D O DO Gudnason V V Wilson J G JG Rotter J I JI Laurie C C CC Psaty B M BM Whitsel E A EA Cupples L A LA Stricker B H BH

The pharmacogenomics journal 20161213 1

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 conduct ...[more]

PMID: 27958378

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Project description:BackgroundThe QT interval and the QT dispersion are currently a subject of considerable interest. Cardiac repolarization delay is known to favor the development of arrhythmias. The QT dispersion, defined as the difference between the longest and the shortest QT intervals or as the standard deviation of the QT duration in the 12-lead ECG is assumed to be reliable predictor of cardiovascular mortality. The seventh annual PhysioNet/Computers in Cardiology Challenge, 2006 addresses a question of high clinical interest: Can the QT interval be measured by fully automated methods with accuracy acceptable for clinical evaluations?MethodThe PTB Diagnostic ECG Database was given to 4 cardiologists and 1 biomedical engineer for manual marking of QRS onsets and T-wave ends in 458 recordings. Each recording consisted of one selected beat in lead II, chosen visually to have minimum baseline shift, noise, and artifact.In cases where no T wave could be observed or its amplitude was very small, the referees were instructed to mark a 'group-T-wave end' taking into consideration leads with better manifested T wave.A modified Delphi approach was used, which included up to three rounds of measurements to obtain results closer to the median.ResultsA total amount of 2*5*548 Q-onsets and T-wave ends were manually marked during round 1. To obtain closer to the median results, 8.58 % of Q-onsets and 3.21 % of the T-wave ends had to be reviewed during round 2, and 1.50 % Q-onsets and 1.17 % T-wave ends in round 3. The mean and standard deviation of the differences between the values of the referees and the median after round 3 were 2.43 +/- 0.96 ms for the Q-onset, and 7.43 +/- 3.44 ms for the T-wave end.ConclusionA fully accessible, on the Internet, dataset of manually measured Q-onsets and T-wave ends was created and presented in additional file: 1 (Table 4) with this article. Thus, an available standard can be used for the development of automated methods for the detection of Q-onsets, T-wave ends and for QT interval measurements.

Dataset Information

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

Publications

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

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