TY - JOUR
T1 - CELF4 variant and anthracycline-related cardiomyopathy
T2 - A children's oncology group genome-wide association study
AU - Wang, Xuexia
AU - Sun, Can Lan
AU - Quiñones-Lombraña, Adolfo
AU - Singh, Purnima
AU - Landier, Wendy
AU - Hageman, Lindsey
AU - Mather, Molly
AU - Rotter, Jerome I.
AU - Taylor, Kent D.
AU - Chen, Yii Der Ida
AU - Armenian, Saro H.
AU - Winick, Naomi
AU - Ginsberg, Jill P.
AU - Neglia, Joseph P.
AU - Oeffinger, Kevin C.
AU - Castellino, Sharon M.
AU - Dreyer, Zoann E.
AU - Hudson, Melissa M.
AU - Robison, Leslie L.
AU - Blanco, Javier G.
AU - Bhatia, Smita
N1 - Publisher Copyright:
© 2016 by American Society of Clinical Oncology.
PY - 2016/3/10
Y1 - 2016/3/10
N2 - Purpose: Interindividual 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. Methods: A 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. Results: No 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/m2 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/m2 or less. This gene-environment interactionwas successfully replicated in an independent set of anthracyclinerelated 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 ofmore than one cTnT variant results in a temporally splitmyofilament 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 ofmore than one TNNT2 splicing variant (90.5% GG v 41.7% GA/AA; P =.005). Conclusion: We 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.
AB - Purpose: Interindividual 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. Methods: A 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. Results: No 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/m2 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/m2 or less. This gene-environment interactionwas successfully replicated in an independent set of anthracyclinerelated 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 ofmore than one cTnT variant results in a temporally splitmyofilament 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 ofmore than one TNNT2 splicing variant (90.5% GG v 41.7% GA/AA; P =.005). Conclusion: We 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.
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U2 - 10.1200/JCO.2015.63.4550
DO - 10.1200/JCO.2015.63.4550
M3 - Article
C2 - 26811534
AN - SCOPUS:84962536066
SN - 0732-183X
VL - 34
SP - 863
EP - 870
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 8
ER -