Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer

• Published in: Pharmacogenetics and genomics Vol. 27; no. 12; pp. 445 - 453
• Main Authors: Ruiz-Pinto, Sara, Pita, Guillermo, Patiño-García, Ana, Alonso, Javier, Pérez-Martínez, Antonio, Cartón, Antonio J, Gutiérrez-Larraya, Federico, Alonso, María R, Barnes, Daniel R, Dennis, Joe, Michailidou, Kyriaki, Gómez-Santos, Carmen, Thompson, Deborah J, Easton, Douglas F, Benítez, Javier, González-Neira, Anna
• Format: Journal Article
• Language: English
• Published: United States 01-12-2017
• Subjects: Adolescent; Anthracyclines - adverse effects; Antineoplastic Agents - adverse effects; Child; Child, Preschool; Exome; Female; Genetic Predisposition to Disease; Heart - drug effects; Humans; Infant; Leukemia - drug therapy; Leukemia - physiopathology; Male; Osteosarcoma - complications; Osteosarcoma - drug therapy; Receptors, G-Protein-Coupled - genetics; Sarcoma, Ewing - complications; Sarcoma, Ewing - drug therapy
• ISSN: 1744-6872; 1744-6880
• DOI: 10.1097/FPC.0000000000000309

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.
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.
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.
Using exome array data, we identified GPR35 as a novel susceptibility gene associated with chronic AIC in pediatric cancer patients.