Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer. Ruiz-Pinto, S., Pita, G., Patiño-García, A., Alonso, J., Pérez-Martínez, A., Cartón, A. J., Gutiérrez-Larraya, F., Alonso, M. R., Barnes, D. R., Dennis, J., Michailidou, K., Gómez-Santos, C., Thompson, D. J., Easton, D. F., Benítez, J., & González-Neira, A. Pharmacogenetics and Genomics, 27(12):445–453, December, 2017.
doi  abstract   bibtex   
OBJECTIVES: Pediatric cancer survivors are a steadily growing population; however, chronic anthracycline-induced cardiotoxicity (AIC) is a serious long-term complication leading to considerable morbidity. We aimed to identify new genes and low-frequency variants influencing the susceptibility to AIC for pediatric cancer patients. PATIENTS AND METHODS: We studied the association of variants on the Illumina HumanExome BeadChip array in 83 anthracycline-treated pediatric cancer patients. In addition to single-variant association tests, we carried out a gene-based analysis to investigate the combined effects of common and low-frequency variants to chronic AIC. RESULTS: Although no single-variant showed an association with chronic AIC that was statistically significant after correction for multiple testing, we identified a novel significant association for G protein-coupled receptor 35 (GPR35) by gene-based testing, a gene with potential roles in cardiac physiology and pathology (P=7.0×10), which remained statistically significant after correction for multiple testing (PFDR=0.03). The greatest contribution to this observed association was made by rs12468485, a missense variant (p.Thr253Met, c.758C\textgreaterT, minor allele frequency=0.04), with the T allele associated with an increased risk of chronic AIC and more severe symptomatic cardiac manifestations at low anthracycline doses. CONCLUSION: Using exome array data, we identified GPR35 as a novel susceptibility gene associated with chronic AIC in pediatric cancer patients.
@article{ruiz-pinto_exome_2017,
	title = {Exome array analysis identifies {GPR35} as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer},
	volume = {27},
	issn = {1744-6880},
	doi = {10.1097/FPC.0000000000000309},
	abstract = {OBJECTIVES: Pediatric cancer survivors are a steadily growing population; however, chronic anthracycline-induced cardiotoxicity (AIC) is a serious long-term complication leading to considerable morbidity. We aimed to identify new genes and low-frequency variants influencing the susceptibility to AIC for pediatric cancer patients.
PATIENTS AND METHODS: We studied the association of variants on the Illumina HumanExome BeadChip array in 83 anthracycline-treated pediatric cancer patients. In addition to single-variant association tests, we carried out a gene-based analysis to investigate the combined effects of common and low-frequency variants to chronic AIC.
RESULTS: Although no single-variant showed an association with chronic AIC that was statistically significant after correction for multiple testing, we identified a novel significant association for G protein-coupled receptor 35 (GPR35) by gene-based testing, a gene with potential roles in cardiac physiology and pathology (P=7.0×10), which remained statistically significant after correction for multiple testing (PFDR=0.03). The greatest contribution to this observed association was made by rs12468485, a missense variant (p.Thr253Met, c.758C{\textgreater}T, minor allele frequency=0.04), with the T allele associated with an increased risk of chronic AIC and more severe symptomatic cardiac manifestations at low anthracycline doses.
CONCLUSION: Using exome array data, we identified GPR35 as a novel susceptibility gene associated with chronic AIC in pediatric cancer patients.},
	language = {eng},
	number = {12},
	journal = {Pharmacogenetics and Genomics},
	author = {Ruiz-Pinto, Sara and Pita, Guillermo and Patiño-García, Ana and Alonso, Javier and Pérez-Martínez, Antonio and Cartón, Antonio J. and Gutiérrez-Larraya, Federico and Alonso, María R. and Barnes, Daniel R. and Dennis, Joe and Michailidou, Kyriaki and Gómez-Santos, Carmen and Thompson, Deborah J. and Easton, Douglas F. and Benítez, Javier and González-Neira, Anna},
	month = dec,
	year = {2017},
	pmid = {28961156},
	keywords = {Adolescent, Anthracyclines, Antineoplastic Agents, Child, Child, Preschool, Exome, Female, Genetic Predisposition to Disease, Heart, Humans, Infant, Leukemia, Male, Osteosarcoma, Receptors, G-Protein-Coupled, Sarcoma, Ewing},
	pages = {445--453},
}

Downloads: 0