Dataset Information

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.

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

SUBMITTER: Noordam R

PROVIDER: S-EPMC5406254 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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 Raymond R Sitlani Colleen M CM Avery Christy L CL Stewart James D JD Gogarten Stephanie M SM Wiggins Kerri L KL Trompet Stella S Warren Helen R HR Sun Fangui F Evans Daniel S DS Li Xiaohui X Li Jin J Smith Albert V AV Bis Joshua C JC Brody Jennifer A JA Busch Evan L EL Caulfield Mark J MJ Chen Yii-Der I YI Cummings Steven R SR Cupples L Adrienne LA Duan Qing Q Franco Oscar H OH Méndez-Giráldez Rául R Harris Tamara B TB Heckbert Susan R SR van Heemst Diana D Hofman Albert A Floyd James S JS Kors Jan A JA Launer Lenore J LJ Li Yun Y Li-Gao Ruifang R Lange Leslie A LA Lin Henry J HJ de Mutsert Renée R Napier Melanie D MD Newton-Cheh Christopher C Poulter Neil N Reiner Alexander P AP Rice Kenneth M KM Roach Jeffrey J Rodriguez Carlos J CJ Rosendaal Frits R FR Sattar Naveed N Sever Peter P Seyerle Amanda A AA Slagboom P Eline PE Soliman Elsayed Z EZ Sotoodehnia Nona N Stott David J DJ Stürmer Til T Taylor Kent D KD Thornton Timothy A TA Uitterlinden André G AG Wilhelmsen Kirk C KC Wilson James G JG Gudnason Vilmundur V Jukema J Wouter JW Laurie Cathy C CC Liu Yongmei Y Mook-Kanamori Dennis O DO Munroe Patricia B PB Rotter Jerome I JI Vasan Ramachandran S RS Psaty Bruce M BM Stricker Bruno H BH Whitsel Eric A EA

Journal of medical genetics 20161230 5

<h4>Background</h4>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.<h4>Methods and results</h4>We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputat ...[more]

PMID: 28039329

Similar Datasets

Project description:BackgroundMigraine, ranked as the 7th-highest specific cause of disability worldwide, has caused an enormous burden on the economy and society. Tricyclic antidepressant (TCA) is one of the most commonly drugs for migraine prevention. However, evidence about the efficacy and tolerability of TCAs in the prophylaxis of migraine in adults is somewhat confusing.MethodsA computerized literature search of the PubMed, Embase, Cochrane, and Web of Science databases from inception to July 2016 was conducted. We reviewed all randomized controlled trials that assigned adults with a clinical diagnosis of migraine to TCAs or other treatments (placebo or other antidepressants). Reduction in migraine frequency or index and response rates to treatment were defined as the efficacy outcomes. Rates of dropout due to adverse effects were defined as the tolerability outcomes.ResultsIn total 12 trials consisting of 1006 participants were identified: 9 trials compared TCAs with placebo, and the other 3 compared amitriptyline with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). A significant advantage of TCAs compared with placebo in the prevention of migraine in adults was observed (standardized mean difference [SMD] = -.75; 95% confidence interval [CI] = -1.05 to -.46; P?<?.00001). Participants receiving TCAs were more likely to experience an ?50% reduction in their headache burden than those receiving placebo (risk ratio [RR] =1.40; 95% CI = 0.89-2.20; P?=?.14). In addition, the efficacy between amitriptyline and SSRIs or SNRIs did not differ for migraine prevention in adults (SMD = -.01; 95% CI = -0.31 to 0.28; P?=?.94) based on the available limited trials. However, TCAs were less well tolerated than placebo (RR = 1.73; 95% CI = 1.00-2.99; P?=?.05) and SSRI or SNRI (RR = 2.85; 95% CI = 0.97-8.41; P?=?.06) on account of adverse events.ConclusionsThis research reveals that TCAs were more effective than placebo, but no more than SSRI or SNRI in ameliorating the headache burden in adults with migraine. However, TCAs appeared to be less tolerated than placebo and SSRIs or SNRIs for some side effects.

Dataset Information

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.

Publications

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets