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
Creators: name: Taylor, Kent D.
name: Rodriguez, Carlos J.
name: Heckbert, Susan R.
name: Warren, Helen R.
name: Gogarten, Stephanie M.
name: Jukema,  Wouter
name: Roach, Jeffrey
name: Méndez-Giráldez, Rául
name: Mook-Kanamori, Dennis O.
name: Franco, Oscar H.
name: Harris, Tamara B.
name: Psaty, Bruce M.
name: van Heemst, Diana
name: Busch, Evan L.
name: Slagboom, P. Eline
name: Liu, Yongmei
name: Stürmer, Til
name: Soliman, Elsayed Z.
name: Hofman, Albert
name: Newton-Cheh, Christopher
name: Rosendaal, Frits R.
name: Trompet, Stella
name: Seyerle, Amanda A.
name: de Mutsert, Renée
name: Sun, Fangui
name: Gudnason, Vilmundur
name: Vasan, Ramachandran S.
name: Sattar, Naveed
name: Caulfield, Mark J.
name: Reiner, Alexander P.
name: Munroe, Patricia B.
name: Sitlani, Colleen M.
name: Laurie, Cathy C.
name: Cupples, L. Adrienne
name: Launer, Lenore J.
name: Kors, Jan A.
name: Lange, Leslie A.
name: Lin, Henry J.
name: Wilson, James G.
name: Stott, David J.
name: Chen, Yii-Der I.
name: Li-Gao, Ruifang
name: Li, Yun
name: Poulter, Neil
name: Noordam, Raymond
name: Napier, Melanie D.
name: Stricker, Bruno H.
name: Uitterlinden, André G.
name: Floyd, James S.
name: Li, Jin
name: Bis, Joshua C.
name: Wilhelmsen, Kirk C.
name: Sever, Peter
name: Smith, Albert V.
name: Rotter, Jerome I.
name: Brody, Jennifer A.
name: Rice, Kenneth M.
name: Thornton, Timothy A.
name: Whitsel, Eric A.
name: Sotoodehnia, Nona
name: Duan, Qing
name: Li, Xiaohui
name: Evans, Daniel S.
name: Wiggins, Kerri L.
name: Stewart, James D.
name: Cummings, Steven R.
name: Avery, Christy L.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2017

description: BACKGROUND: Increased 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 RESULTS: We 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.

CONCLUSIONS: Among 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.