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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.

Publication ,  Journal Article
Noordam, R; Sitlani, CM; Avery, CL; Stewart, JD; Gogarten, SM; Wiggins, KL; Trompet, S; Warren, HR; Sun, F; Evans, DS; Li, X; Li, J; Bis, JC ...
Published in: J Med Genet
May 2017

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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Published In

J Med Genet

DOI

EISSN

1468-6244

Publication Date

May 2017

Volume

54

Issue

5

Start / End Page

313 / 323

Location

England

Related Subject Headings

  • Pharmacogenetics
  • Middle Aged
  • Male
  • Humans
  • Heart
  • Genome-Wide Association Study
  • Genetics & Heredity
  • Genetic Loci
  • Female
  • Electrocardiography
 

Citation

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Noordam, R., Sitlani, C. M., Avery, C. L., Stewart, J. D., Gogarten, S. M., Wiggins, K. L., … Whitsel, E. A. (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. J Med Genet, 54(5), 313–323. https://doi.org/10.1136/jmedgenet-2016-104112
Noordam, Raymond, Colleen M. Sitlani, Christy L. Avery, James D. Stewart, Stephanie M. Gogarten, Kerri L. Wiggins, Stella Trompet, et al. “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.J Med Genet 54, no. 5 (May 2017): 313–23. https://doi.org/10.1136/jmedgenet-2016-104112.
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. 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. J Med Genet. 2017 May;54(5):313–323.

Published In

J Med Genet

DOI

EISSN

1468-6244

Publication Date

May 2017

Volume

54

Issue

5

Start / End Page

313 / 323

Location

England

Related Subject Headings

  • Pharmacogenetics
  • Middle Aged
  • Male
  • Humans
  • Heart
  • Genome-Wide Association Study
  • Genetics & Heredity
  • Genetic Loci
  • Female
  • Electrocardiography