A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23

Abstract

Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome-wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D ' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 × 10(-10) and P = 6.07 × 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.

Figure 1.

Forest plot showing the association of rs718314 and rs1049380 with RCC risk in discovery and validation populations and in meta-analysis.

Figure 2.

(A) Results of SNP association from primary scan: observed results from genotyped SNPs are in red and imputed results are in black. All known genes in this region are also shown. (B) LD structure across this region based on genotyped and imputed SNPs. Shown in each box is the square of the correlation coefficient (r²) derived from genotyped and imputed SNPs in Haploview software. Darker shading box indicates greater extent of LD between two SNPs.