Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer.
Cartón, Antonio J
Alonso, María R
Pharmacogenetics and Genomics
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Ruiz-Pinto, S., Pita, G., Patiño-García, A., Alonso, J., Pérez-Martínez, A., Cartón, A. J., Gutiérrez-Larraya, F., et al. (2017). Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer.. Pharmacogenetics and Genomics, 27 (12), 445-453. https://doi.org/10.1097/FPC.0000000000000309
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.
This work was supported by the Spanish Association against Cancer (AECC: Asociación Española contra el Cáncer). Human Genotyping lab is a member of CeGen, PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+i 2013-2016, funded by ISCIII and FEDER (Fondo Europeo de Desarrollo Regional). Sara Ruiz-Pinto is a predoctoral fellow supported by the Severo Ochoa Excellence Programme (Project SEV-2011-0191).
Cancer Research UK (16563)
External DOI: https://doi.org/10.1097/FPC.0000000000000309
This record's URL: https://www.repository.cam.ac.uk/handle/1810/274616