1. CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children’s Oncology Group Genome-Wide Association Study
- Author
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Wang, Xuexia, Sun, Can-Lan, Quiñones-Lombraña, Adolfo, Singh, Purnima, Landier, Wendy, Hageman, Lindsey, Mather, Molly, Rotter, Jerome I, Taylor, Kent D, Chen, Yii-Der Ida, Armenian, Saro H, Winick, Naomi, Ginsberg, Jill P, Neglia, Joseph P, Oeffinger, Kevin C, Castellino, Sharon M, Dreyer, Zoann E, Hudson, Melissa M, Robison, Leslie L, Blanco, Javier G, and Bhatia, Smita
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Pediatric ,Rare Diseases ,Genetics ,Cardiovascular ,Cancer ,Biotechnology ,Human Genome ,Prevention ,Heart Disease ,Clinical Research ,Aetiology ,2.1 Biological and endogenous factors ,Adolescent ,Adult ,Anthracyclines ,CELF Proteins ,Cardiomyopathies ,Case-Control Studies ,Child ,Child ,Preschool ,Dose-Response Relationship ,Drug ,Female ,Genome-Wide Association Study ,Humans ,Infant ,Infant ,Newborn ,Male ,Polymorphism ,Single Nucleotide ,Protein Isoforms ,Troponin T ,Young Adult ,Clinical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
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.
- Published
- 2016