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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.

TitleA 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 TypePublication
Year2017
AuthorsNoordam 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, L Cupples A, 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, P Slagboom E, Soliman EZ, Sotoodehnia N, Stott DJ, Stürmer T, Taylor KD, Thornton TA, Uitterlinden AG, Wilhelmsen KC, Wilson JG, Gudnason V, J Jukema W, Laurie CC, Liu Y, Mook-Kanamori DO, Munroe PB, Rotter JI, Vasan RS, Psaty BM, Stricker BH, Whitsel EA
JournalJ Med Genet
Volume54
Issue5
Pagination313-323
Date Published2017 05
ISSN1468-6244
KeywordsAged, aging, Antidepressive Agents, Tricyclic, Electrocardiography, Female, Genetic Loci, genome-wide association study, Heart, Humans, Male, Middle Aged, Pharmacogenetics
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 (β=56.3, p=3.9e) and rs9830388 in (β=25.2, p=1.7e). In Hispanic/Latino cohorts, rs2291477 in significantly modified the association between TCAs and QT intervals (β=9.3, p=2.55e). 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>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 and were identified in relation to RR intervals. Among Hispanic/Latinos, variants in modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

DOI10.1136/jmedgenet-2016-104112
Alternate JournalJ Med Genet
PubMed ID28039329
PubMed Central IDPMC5406254
Grant ListR01 HL103612 / HL / NHLBI NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
P01 GM099568 / GM / NIGMS NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
T32 CA009001 / CA / NCI NIH HHS / United States
MR/K006584/1 / MRC_ / Medical Research Council / United Kingdom
U01 HL120393 / HL / NHLBI NIH HHS / United States
Z01 AG007380-02 / ImNIH / Intramural NIH HHS / United States
MS#: 
0365
Manuscript Lead/Corresponding Author Affiliation: 
HCHS/SOL Genetic Analysis Center - University of Washington, Seattle
ECI: 
Yes
Manuscript Status: 
Published