Journal
PHARMACOGENETICS AND GENOMICS
Volume 27, Issue 12, Pages 445-453Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FPC.0000000000000309
Keywords
anthracycline; chronic cardiotoxicity; coding variants; GPR35; low-frequency variants; pediatric cancer survivors
Funding
- Spanish Association against Cancer (AECC: Asociacion Espanola contra el Cancer)
- PE I+D+i - ISCIII [PT13/0001]
- FEDER (Fondo Europeo de Desarrollo Regional)
- Severo Ochoa Excellence Programme [SEV-2011-0191]
- Cancer Research UK [16563] Funding Source: researchfish
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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.
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