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

作者：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; Mendez Giraldez Raul; Harris Tamara B; Heckbert Susan R; van Heemst Diana; Hofman Albert

来源：Journal of Medical Genetics, 2017, 54(5): 313-323.

DOI：10.1136/jmedgenet-2016-104112

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 (beta=56.3, p(interaction)=3.9e(-9)) and rs9830388 in UBE2E2 (beta=25.2, p(interaction)=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (beta=9.3, p(interaction)=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 (p(interaction)>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.

• 出版日期2017-5
• 单位UCLA