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Published on: June 7, 2018
Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in
Sara Ruiz-Pinto1, Guillermo Pita, Ana Patiño-García
1aHuman Genotyping Unit-CeGen bHuman Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO) cPediatric Solid Tumor Laboratory, Human Genetic Department, Research Institute of Rare Diseases, Instituto de Salud Carlos III dDepartment of Pediatric Hemato-Oncology eDepartment of Pediatric Cardiology, Hospital Universitario La Paz fDepartment of Pediatrics, Hospital Universitario Infanta Elena, Madrid gDepartment of Pediatrics, University Clinic of Navarra, Universidad de Navarra, Pamplona, Spain hDepartment of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology iDepartment of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK jDepartment of Electron Microscopy/Molecular Pathology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
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>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.
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