Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer. Issue 12 (December 2017)

• Record Type: Journal Article
• 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
• Is Part Of: Pharmaocogenetics and genomics. Volume 27:Issue 12(2017:Dec.)
• Publication Date: 2017-12
• Subjects: anthracycline -- chronic cardiotoxicity -- coding variants -- GPR35 -- low-frequency variants -- pediatric cancer survivors; Pharmacogenetics -- Periodicals; Pharmacogenomics -- Periodicals; Genetic toxicology -- Periodicals; Biomedical genetics -- Periodicals; 615.7
• DOI: 10.1097/FPC.0000000000000309
• Languages: English
• ISSNs: 1744-6872

Abstract

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 −6 ), which remained statistically significant after correction for multiple testing ( P FDR =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. Abstract : Supplemental Digital Content is available in the text.