Key result
TCA use interacted with variants in BRE (P=3.9e-9) and UBE2E2 (P=1.7e-8) to affect RR intervals in Europeans, and with TGFBR3 (P=2.55e-8) to affect QT intervals in Hispanic/Latinos.
Why the study?
Do specific genetic loci modify the association between tricyclic/tetracyclic antidepressant use and resting RR and QT intervals in diverse ethnic populations?
Observational (n=69,749)
Yes
Do specific genetic loci modify the association between tricyclic/tetracyclic antidepressant use and resting RR and QT intervals in diverse ethnic populations?
Specific genetic variants in BRE, UBE2E2, and TGFBR3 modify the effect of tricyclic/tetracyclic antidepressants on resting RR and QT intervals in a race/ethnic-specific manner.
TCA-gene interactions on ECG intervals are hypothesis-generating; leaves open clinical arrhythmia risk or prescribing implications.
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.
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Noordam et al. (2016) reported an observational. Tricyclic/tetracyclic antidepressants (TCAs) vs. Non-users or different genotypes was evaluated on Resting RR and QT intervals (β=56.3, p=3.9e-9). TCA use interacted with variants in BRE (P=3.9e-9) and UBE2E2 (P=1.7e-8) to affect RR intervals in Europeans, and with TGFBR3 (P=2.55e-8) to affect QT intervals in Hispanic/Latinos.
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