Abstract
Abstract Many previous association studies have been addressed genetic variations in obesity related genes on breast cancer risk, however, limited consideration of genes and gene-environmental interaction was involved. We investigated the associations of known obesity-related genes on breast cancer risk by comprehensive assessment based on individual SNP analysis and gene-based pathway-analysis. This study was conducted in 1,786 cases and 1,789 controls from Seoul Breast Cancer Study (SEBCS), a multicenter case-control study. The selection of 1,561 candidate obesity-related gene for this study was involved based on GWAS catalog and previous published data associated with obesity. Associations of single-nucleotide polymorphism (SNP) with BMI were assessed by linear regression models under an additive genetic model adjusting for age and disease status to identify genetic loci for obesity. 2,366 BMI-related significant SNPs including additional significant 449 SNPs which independently associated with BMI in our data (p<10-4) were evaluated for the genetic effect on breast cancer risk. Per-allele odds ratio for breast cancer risk was assessed using logistic regression models adjusting for age and 1st family history of breast cancer. Gene-based pathway significance was assessed by the adaptive rank-truncated product (ARTP) method with 1,000 permutations for association between BMI-related genes and breast cancer risk. Among available 227,197 SNPs from candidate genes and additional significant SNPs in SEBCS data, 12,388 SNPs in 890 genes were found to be associated with BMI (p<0.05): 495 genes (55.7%) from GWAS catalog and 281 genes (48.4%) from published candidate genes for obesity were identified, respectively. Rs17804012 in RBFOX1 and rs2014791 in LINC00317 showed the most significant association with BMI (p<5E-6), which observed null association with breast cancer risk. In contrast, the gene-based pathway analysis including less significantly associated genes with BMI (N=644, p<0.05) showed significant association with breast cancer risk (the pathway p=0.003). Especially, the effect of THRB gene on breast cancer risk has highly significant value (p=9E-04) and the association was confined to premenopausal women with BMI above 23.2 (p<0.01). The group of BMI-related genes including THRB was significantly associated with breast cancer risk in pathway analysis and the associations were different depending on the menopausal status and/or BMI levels. Our results suggest that consideration of the complex genetic pathway related to environmental factors might reveal additional breast cancer susceptibility loci. Citation Format: Seokang Chung, Nan Song, Hyuna Sung, Sue K. Park, Wonshik Han, Dong-Young Noh, Sei-Hyun Ahn, Keun-Young Yoo, Daehee Kang, Ji-Yeob Choi. Genetic variation in obesity-related genes and breast cancer risk in the Seoul Breast Cancer Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3273. doi:10.1158/1538-7445.AM2014-3273
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