Xuexia Wang1, Can-Lan Sun1, Adolfo Quiñones-Lombraña1, Purnima Singh1, Wendy Landier1, Lindsey Hageman1, Molly Mather1, Jerome I Rotter1, Kent D Taylor1, Yii-Der Ida Chen1, Saro H Armenian1, Naomi Winick1, Jill P Ginsberg1, Joseph P Neglia1, Kevin C Oeffinger1, Sharon M Castellino1, Zoann E Dreyer1, Melissa M Hudson1, Leslie L Robison1, Javier G Blanco1, Smita Bhatia2. 1. Xuexia Wang, University of Wisconsin-Milwaukee, Milwaukee, WI; Can-Lan Sun, Molly Mather, Saro H. Armenian, City of Hope, Duarte; Jerome I. Rotter, Kent D. Taylor, Yii-Der Ida Chen, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles, Torrance, CA; Adolfo Quiñones-Lombraña, Javier G. Blanco, State University of New York at Buffalo, Buffalo; Kevin C. Oeffinger, Memorial Sloan Kettering Cancer Center, New York, NY; Purnima Singh, Wendy Landier, Lindsey Hageman, Smita Bhatia, University of Alabama at Birmingham, Birmingham, AL; Naomi Winick, University of Texas Southwestern Medical Center, Dallas; Zoann E. Dreyer, Texas Children's Cancer Center, Houston, TX; Jill P. Ginsberg, Childrens Hospital of Philadelphia, Philadelphia, PA; Joseph P. Neglia, University of Minnesota, Minneapolis, MN; Sharon M. Castellino, Emory University and Children's Healthcare of Atlanta, Atlanta, GA; and Melissa M. Hudson, Leslie L. Robison, St Jude Children's Research Hospital, Memphis, TN. 2. Xuexia Wang, University of Wisconsin-Milwaukee, Milwaukee, WI; Can-Lan Sun, Molly Mather, Saro H. Armenian, City of Hope, Duarte; Jerome I. Rotter, Kent D. Taylor, Yii-Der Ida Chen, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles, Torrance, CA; Adolfo Quiñones-Lombraña, Javier G. Blanco, State University of New York at Buffalo, Buffalo; Kevin C. Oeffinger, Memorial Sloan Kettering Cancer Center, New York, NY; Purnima Singh, Wendy Landier, Lindsey Hageman, Smita Bhatia, University of Alabama at Birmingham, Birmingham, AL; Naomi Winick, University of Texas Southwestern Medical Center, Dallas; Zoann E. Dreyer, Texas Children's Cancer Center, Houston, TX; Jill P. Ginsberg, Childrens Hospital of Philadelphia, Philadelphia, PA; Joseph P. Neglia, University of Minnesota, Minneapolis, MN; Sharon M. Castellino, Emory University and Children's Healthcare of Atlanta, Atlanta, GA; and Melissa M. Hudson, Leslie L. Robison, St Jude Children's Research Hospital, Memphis, TN. sbhatia@peds.uab.edu.
Abstract
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/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). 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.
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/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). 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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