Detalle Publicación


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

Autores: Ruiz-Pinto, S.; Pita, G.; Patiño García, Ana; Alonso, J.; Perez-Martinez, A.; Carton, A. J. ; Gutierrez-Larraya, F. ; Alonso, M. R. ; Barnes, D. R. ; Dennis, J.; Michailidou, K.; Gomez-Santos, C.; Thompson, D. J. ; Easton, D. F.; Benitez, J.; Gonzalez-Neira, A.
ISSN: 1744-6872
Volumen: 27
Número: 12
Páginas: 445 - 453
Fecha de publicación: 2017
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 x 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. Copyright (c) 2017 Wolters Kluwer Health, Inc. All rights reserved.