학술논문
A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium
Document Type
article
Author
Noordam, Raymond; Sitlani, Colleen M; Avery, Christy L; Stewart, James D; Gogarten, Stephanie M; Wiggins, Kerri L; Trompet, Stella; Warren, Helen R; Sun, Fangui; Evans, Daniel S; Li, Xiaohui; Li, Jin; Smith, Albert V; Bis, Joshua C; Brody, Jennifer A; Busch, Evan L; Caulfield, Mark J; Chen, Yii-Der I; Cummings, Steven R; Cupples, L Adrienne; Duan, Qing; Franco, Oscar H; Méndez-Giráldez, Rául; Harris, Tamara B; Heckbert, Susan R; van Heemst, Diana; Hofman, Albert; Floyd, James S; Kors, Jan A; Launer, Lenore J; Li, Yun; Li-Gao, Ruifang; Lange, Leslie A; Lin, Henry J; de Mutsert, Renée; Napier, Melanie D; Newton-Cheh, Christopher; Poulter, Neil; Reiner, Alexander P; Rice, Kenneth M; Roach, Jeffrey; Rodriguez, Carlos J; Rosendaal, Frits R; Sattar, Naveed; Sever, Peter; Seyerle, Amanda A; Slagboom, P Eline; Soliman, Elsayed Z; Sotoodehnia, Nona; Stott, David J; Stürmer, Til; Taylor, Kent D; Thornton, Timothy A; Uitterlinden, André G; Wilhelmsen, Kirk C; Wilson, James G; Gudnason, Vilmundur; Jukema, J Wouter; Laurie, Cathy C; Liu, Yongmei; Mook-Kanamori, Dennis O; Munroe, Patricia B; Rotter, Jerome I; Vasan, Ramachandran S; Psaty, Bruce M; Stricker, Bruno H; Whitsel, Eric A
Source
Journal of Medical Genetics. 54(5)
Subject
Language
Abstract
BackgroundIncreased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.Methods and resultsWe conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e-9) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e-8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e-8). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.ConclusionsAmong Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.