Potential Susceptibility Loci Identified for Renal Cell Carcinoma by Targeting Obesity-Related Genes.

Obesity is an established risk factor for renal cell carcinoma (RCC). Although genome-wide association studies (GWAS) of RCC have identified several susceptibility loci, additional variants might be missed due to the highly conservative selection. We conducted a multiphase study utilizing three independent genome-wide scans at MD Anderson Cancer Center (MDA RCC GWAS and MDA RCC OncoArray) and National Cancer Institute (NCI RCC GWAS), which consisted of a total of 3,530 cases and 5,714 controls, to investigate genetic variations in obesity-related genes and RCC risk. In the discovery phase, 32,946 SNPs located at ±10 kb of 2,001 obesity-related genes were extracted from MDA RCC GWAS and analyzed using multivariable logistic regression. Proxies ( > 0.8) were searched or imputation was performed if SNPs were not directly genotyped in the validation sets. Twenty-one SNPs with < 0.05 in both MDA RCC GWAS and NCI RCC GWAS were subsequently evaluated in MDA RCC OncoArray. In the overall meta-analysis, significant ( < 0.05) associations with RCC risk were observed for SNP mapping to [rs10521506-G: OR = 0.87 (0.81-0.93), = 2.33 × 10], [rs2229536-A: OR = 0.87 (0.81-0.93), = 2.33 × 10], [rs4601989-A: OR = 0.86 (0.80-0.93), = 2.71 × 10], [rs10850596-A: OR = 1.14 (1.07-1.23), = 1.50 × 10], and [rs3761840-G: OR = 0.90 (0.85-0.97), = 2.47 × 10]. We did not observe any significant cis-expression quantitative trait loci effect for these SNPs in the TCGA KIRC data. Taken together, we found that genetic variation of obesity-related genes could influence RCC susceptibility. The five identified loci may provide new insights into disease etiology that reveal importance of obesity-related genes in RCC development. .