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.
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.
Noordam, R; Sitlani, CM; Avery, CL; Stewart, JD; Gogarten, SM; Wiggins, KL; Trompet, S; Warren, HR; Sun, F; Evans, DS; Li, X; Li, J; Smith, AV; Bis, JC; Brody, JA; Busch, EL; Caulfield, MJ; Chen, Y-DI; Cummings, SR; Cupples, LA; Duan, Q; Franco, OH; Méndez-Giráldez, R; Harris, TB; Heckbert, SR; van Heemst, D; Hofman, A; Floyd, JS; Kors, JA; Launer, LJ; Li, Y; Li-Gao, R; Lange, LA; Lin, HJ; de Mutsert, R; Napier, MD; Newton-Cheh, C; Poulter, N; Reiner, AP; Rice, KM; Roach, J; Rodriguez, CJ; Rosendaal, FR; Sattar, N; Sever, P; Seyerle, AA; Slagboom, PE; Soliman, EZ; Sotoodehnia, N; Stott, DJ; Stürmer, T; Taylor, KD; Thornton, TA; Uitterlinden, AG; Wilhelmsen, KC; Wilson, JG; Gudnason, V; Jukema, JW; Laurie, CC; Liu, Y; Mook-Kanamori, DO; Munroe, PB; Rotter, JI; Vasan, RS; Psaty, BM; Stricker, BH; Whitsel, EA
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