CELF4 variant and anthracycline-related cardiomyopathy: A children's oncology group genome-wide association study

Xuexia Wang, Can Lan Sun, Adolfo Quiñones-Lombraña, Purnima Singh, Wendy Landier, Lindsey Hageman, Molly Mather, Jerome I. Rotter, Kent D. Taylor, Yii Der Ida Chen, Saro H. Armenian, Naomi Winick, Jill P. Ginsberg, Joseph P. Neglia, Kevin C. Oeffinger, Sharon M. Castellino, Zoann E. Dreyer, Melissa M. Hudson, Leslie L. Robison, Javier G. BlancoSmita Bhatia

Research output: Contribution to journalArticle

24 Citations (Scopus)

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/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.

Original languageEnglish (US)
Pages (from-to)863-870
Number of pages8
JournalJournal of Clinical Oncology
Volume34
Issue number8
DOIs
StatePublished - Mar 10 2016

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Genome-Wide Association Study
Anthracyclines
Cardiomyopathies
Single Nucleotide Polymorphism
Troponin T
Genotype
Genes
Gene-Environment Interaction
Genetic Predisposition to Disease
Survivors
Neoplasms
Thorax
Biomarkers
Alleles
Radiation
Calcium
Wounds and Injuries

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Wang, X., Sun, C. L., Quiñones-Lombraña, A., Singh, P., Landier, W., Hageman, L., ... Bhatia, S. (2016). CELF4 variant and anthracycline-related cardiomyopathy: A children's oncology group genome-wide association study. Journal of Clinical Oncology, 34(8), 863-870. https://doi.org/10.1200/JCO.2015.63.4550

CELF4 variant and anthracycline-related cardiomyopathy : A children's oncology group genome-wide association study. / 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.; Bhatia, Smita.

In: Journal of Clinical Oncology, Vol. 34, No. 8, 10.03.2016, p. 863-870.

Research output: Contribution to journalArticle

Wang, X, Sun, CL, Quiñones-Lombraña, A, Singh, P, Landier, W, Hageman, L, Mather, M, Rotter, JI, Taylor, KD, Chen, YDI, Armenian, SH, Winick, N, Ginsberg, JP, Neglia, JP, Oeffinger, KC, Castellino, SM, Dreyer, ZE, Hudson, MM, Robison, LL, Blanco, JG & Bhatia, S 2016, 'CELF4 variant and anthracycline-related cardiomyopathy: A children's oncology group genome-wide association study', Journal of Clinical Oncology, vol. 34, no. 8, pp. 863-870. https://doi.org/10.1200/JCO.2015.63.4550
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. ; Bhatia, Smita. / CELF4 variant and anthracycline-related cardiomyopathy : A children's oncology group genome-wide association study. In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 8. pp. 863-870.
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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/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.",
author = "Xuexia Wang and Sun, {Can Lan} and Adolfo Qui{\~n}ones-Lombra{\~n}a and Purnima Singh and Wendy Landier and Lindsey Hageman and Molly Mather and Rotter, {Jerome I.} and Taylor, {Kent D.} and Chen, {Yii Der Ida} and Armenian, {Saro H.} and Naomi Winick and Ginsberg, {Jill P.} and Neglia, {Joseph P.} and Oeffinger, {Kevin C.} and Castellino, {Sharon M.} and Dreyer, {Zoann E.} and Hudson, {Melissa M.} and Robison, {Leslie L.} and Blanco, {Javier G.} and Smita Bhatia",
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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

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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