Abstract 2544: Potential gene variants associated with obesity following cranial radiation treatment for childhood cancer in a genome-wide association study.

Abstract

Abstract Survivors of childhood cancer who were exposed to cranial radiation during curative treatment are at high risk for obesity. Obesity is problematic in this population because it may add to the survivors’ already elevated risk for chronic diseases, including those with significant potential for premature mortality, like heart disease and some types of secondary cancers. Previous studies have suggested that genetic differences in response to anticancer therapies can influence the development of long-term adverse health effects in cancer survivors. Therefore, the aim of this study was to identify single nucleotide polymorphisms (SNPs) associated with obesity among survivors of childhood cancer using a genome-wide association study analysis. Participants included 1468 (714 male) adults previously treated for childhood cancer at St. Jude Children's Research Hospital (SJCRH) who survived ≥10 years from diagnosis. All participants underwent clinical evaluation at SJCRH and provided a DNA sample. Genotyping was conducted using the Affymetrix Genome-Wide Human SNP 6.0 Array. Imputation of SNPs not included on the array was performed using MACH (Version 1.0.18.c) and data from the 1000 Genomes Project was used as a reference panel. Obesity was defined as a body mass index (BMI) ≥30kg/m2. The cohort was stratified into two groups for analyses: survivors treated with cranial radiation (N=597) and survivors treated without cranial radiation (N=871). Logistic regression models, implemented in PLINK (Version 1.07) and mach2dat (Version v120), were used to identify potential SNPs associated with the obesity outcome. Over half (51%) of survivors treated with cranial radiation had a BMI≥30kg/m2 compared with 39% of survivors who did not receive cranial radiation. Among survivors previously treated with cranial radiation, multiple SNPs within the glycine receptor α 3 gene (GLRA3) were found to be associated with obesity (p<5 x 10−8). The strongest association with obesity was observed for SNP rs12641804 (p=3.9 x 10−10). In contrast, we did not observe an association between SNPs located within GLRA3 and obesity among survivors who did not receive cranial radiation, nor did any other SNP reach genome-wide significance (p<5 x 10−8) in this model. GLRA3 codes for a membrane-bound receptor protein involved in signaling by the neurotransmitter glycine. Our data suggest a possible role for glycine receptors in the pathogenesis of obesity among survivors of childhood cancer following cranial irradiation. Validation of our findings in an independent cohort is required. Citation Format: Carmen L. Wilson, Wei Liu, Geoffrey Neale, Deokumar Srivastava, James G. Gurney, Guolian Kang, Perdeep Mehta, Rohit Ojha, Melissa M. Hudson, Leslie L. Robison, Kirsten K. Ness. Potential gene variants associated with obesity following cranial radiation treatment for childhood cancer in a genome-wide association study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2544. doi:10.1158/1538-7445.AM2013-2544