Dataset Information

Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults.

ABSTRACT: BACKGROUND:Anthracyclines are important chemotherapeutic agents, but their use is limited by cardiotoxicity. Candidate gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity and heart failure, but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular (LV) function. The purpose of this study was to identify genetic factors influencing changes in LV function after anthracycline chemotherapy. METHODS:We conducted a genome-wide association study (GWAS) of change in LV function after anthracycline exposure in 385 patients identified from BioVU, a resource linking DNA samples to de-identified electronic medical record data. Variants with P values less than 1×10 were independently tested for replication in a cohort of 181 anthracycline-exposed patients from a prospective clinical trial. Pathway analysis was performed to assess combined effects of multiple genetic variants. RESULTS:Both cohorts were middle-aged adults of predominantly European descent. Among 11 candidate loci identified in discovery GWAS, one single nucleotide polymorphism near PR domain containing 2, with ZNF domain (PRDM2), rs7542939, had a combined P value of 6.5×10 in meta-analysis. Eighteen Kyoto Encyclopedia of Gene and Genomes pathways showed strong enrichment for variants associated with the primary outcome. Identified pathways related to DNA repair, cellular metabolism, and cardiac remodeling. CONCLUSION:Using genome-wide association we identified a novel candidate susceptibility locus near PRDM2. Variation in genes belonging to pathways related to DNA repair, metabolism, and cardiac remodeling may influence changes in LV function after anthracycline exposure.

SUBMITTER: Wells QS

PROVIDER: S-EPMC5502740 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults.

Wells Quinn S QS Veatch Olivia J OJ Fessel Joshua P JP Joon Aron Y AY Levinson Rebecca T RT Mosley Jonathan D JD Held Elizabeth P EP Lindsay Chase S CS Shaffer Christian M CM Weeke Peter E PE Glazer Andrew M AM Bersell Kevin R KR Van Driest Sara L SL Karnes Jason H JH Blair Marcia A MA Lagrone Lore W LW Su Yan R YR Bowton Erica A EA Feng Ziding Z Ky Bonnie B Lenihan Daniel J DJ Fisch Michael J MJ Denny Joshua C JC Roden Dan M DM

Pharmacogenetics and genomics 20170701 7

<h4>Background</h4>Anthracyclines are important chemotherapeutic agents, but their use is limited by cardiotoxicity. Candidate gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity and heart failure, but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular (LV) function. The purpose of this study was to identify genetic factors influencing changes in LV functi ...[more]

PMID: 28542097

Similar Datasets

Project description:BackgroundExperimental and clinical studies show that prematurity leads to altered left ventricular (LV) structure and function with preserved resting LV ejection fraction (EF). Large-scale epidemiological data now links prematurity to increased early heart failure risk.ObjectivesThe authors performed echocardiographic imaging at prescribed exercise intensities to determine whether preterm-born adults have impaired LV functional response to physical exercise.MethodsWe recruited 101 normotensive young adults born preterm (n = 47; mean gestational age 32.8 ± 3.2 weeks) and term (n = 54) for detailed cardiovascular phenotyping. Full clinical resting and exercise stress echocardiograms were performed, with apical 4-chamber views collected while exercising at 40%, 60%, and 80% of peak exercise capacity, determined by maximal cardiopulmonary exercise testing.ResultsPreterm-born individuals had greater LV mass (p = 0.015) with lower peak systolic longitudinal strain (p = 0.038) and similar EF to term-born control subjects at rest (p = 0.62). However, by 60% exercise intensity, EF was 6.7% lower in preterm subjects (71.9 ± 8.7% vs 78.6 ± 5.4%; p = 0.004) and further declined to 7.3% below the term-born group at 80% exercise intensity (69.8 ± 6.4% vs 77.1 ± 6.3%; p = 0.004). Submaximal cardiac output reserve was 56% lower in preterm-born subjects versus term-born control subjects at 40% of peak exercise capacity (729 ± 1,162 ml/min/m2 vs. 1,669 ± 937 ml/min/m2; p = 0.021). LV length and resting peak systolic longitudinal strain predicted EF increase from rest to 60% exercise intensity in the preterm group (r = 0.68, p = 0.009 and r = 0.56, p = 0.031, respectively).ConclusionsPreterm-born young adults had impaired LV response to physiological stress when subjected to physical exercise, which suggested a reduced myocardial functional reserve that might help explain their increased risk of early heart failure. (Young Adult Cardiovascular Health sTudy [YACHT]; NCT02103231).

Project description:PurposeInterindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests that genetic susceptibility could play a role. The current study uses an agnostic approach to identify genetic variants that could modify cardiomyopathy risk.MethodsA genome-wide association study was conducted in childhood cancer survivors with and without cardiomyopathy (cases and controls, respectively). Single-nucleotide polymorphisms (SNPs) that surpassed a prespecified threshold for statistical significance were independently replicated. The possible mechanistic significance of validated SNP(s) was sought by using healthy heart samples.ResultsNo SNP was marginally associated with cardiomyopathy. However, SNP rs1786814 on the CELF4 gene passed the significance cutoff for gene-environment interaction (Pge = 1.14 × 10(-5)). Multivariable analyses adjusted for age at cancer diagnosis, sex, anthracycline dose, and chest radiation revealed that, among patients with the A allele, cardiomyopathy was infrequent and not dose related. However, among those exposed to greater than 300 mg/m(2) of anthracyclines, the rs1786814 GG genotype conferred a 10.2-fold (95% CI, 3.8- to 27.3-fold; P < .001) increased risk of cardiomyopathy compared with those who had GA/AA genotypes and anthracycline exposure of 300 mg/m(2) or less. This gene-environment interaction was successfully replicated in an independent set of anthracycline-related cardiomyopathy. CUG-BP and ETR-3-like factor proteins control developmentally regulated splicing of TNNT2, the gene that encodes for cardiac troponin T (cTnT), a biomarker of myocardial injury. Coexistence of more than one cTnT variant results in a temporally split myofilament response to calcium, which causes decreased contractility. Analysis of TNNT2 splicing variants in healthy human hearts suggested an association between the rs1786814 GG genotype and coexistence of more than one TNNT2 splicing variant (90.5% GG v 41.7% GA/AA; P = .005).ConclusionWe report a modifying effect of a polymorphism of CELF4 (rs1786814) on the dose-dependent association between anthracyclines and cardiomyopathy, which possibly occurs through a pathway that involves the expression of abnormally spliced TNNT2 variants.

Dataset Information

Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults.

Publications

Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets