title: 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.
authors.affiliation: Deparments of Epidemiology and Medicine, University of Washington, Seattle, WA, USA.
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authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
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authors.identifier: 0000-0002-5037-3572
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mesh_terms: D000368:Aged; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D004562:Electrocardiography / Q000187:drug effects*; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D000071185:Pharmacogenomic Testing / Q000379:methods; D013453:Sulfonylurea Compounds / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D013453:Sulfonylurea Compounds; D065729:Cytochrome P-450 CYP2C9