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

Noordam, R. et al. (2017) 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. Journal of Medical Genetics, 54(5), pp. 313-323. (doi: 10.1136/jmedgenet-2016-104112) (PMID:28039329)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Stott J, Professor David and Sattar, Professor Naveed
• Authors: Noordam, R., Sitlani, C. M., Avery, C. L., Stewart, J. D., Gogarten, S. M., Wiggins, K. L., Trompet, S., Warren, H. R., Sun, F., Evans, D. S., Li, X., Li, J., Smith, A. V., Bis, J. C., Brody, J. A., Busch, E. L., Caulfield, M. J., Chen, Y.-D. I., Cummings, S. R., Cupples, L. A., Duan, Q., Franco, O. H., Méndez-Giráldez, R., Harris, T. B., Heckbert, S. R., van Heemst, D., Hofman, A., Floyd, J. S., Kors, J. A., Launer, L. J., Li, Y., Li-Gao, R., Lange, L. A., Lin, H. J., de Mutsert, R., Napier, M. D., Newton-Cheh, C., Poulter, N., Reiner, A. P., Rice, K. M., Roach, J., Rodriguez, C. J., Rosendaal, F. R., Sattar, N., Sever, P., Seyerle, A. A., Slagboom, P. E., Soliman, E. Z., Sotoodehnia, N., Stott, D. J., Stürmer, T., Taylor, K. D., Thornton, T. A., Uitterlinden, A. G., Wilhelmsen, K. C., Wilson, J. G., Gudnason, V., Jukema, J. W., Laurie, C. C., Liu, Y., Mook-Kanamori, D. O., Munroe, P. B., Rotter, J. I., Vasan, R. S., Psaty, B. M., Stricker, B. H., and Whitsel, E. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of Medical Genetics
• Publisher: BMJ Publishing Group
• ISSN: 0022-2593
• ISSN (Online): 1468-6244
• Published Online: 30 December 2016
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Journal of Medical Genetics 54(5):313-323
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher