Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3

Abstract

We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r² = 0.99 in controls), rs11894252 (P = 1.8 × 10⁻⁸) and rs7579899 (P = 2.3 × 10⁻⁹), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 × 10⁻¹⁴). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 × 10⁻⁸). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiological insights.

Figure 1. Association results, recombination and linkage disequilibrium plots for three regions achieving genome-wide significance in RCC GWAS

Results of pooled IARC/CNG and NCI GWAS data (GWAS), and for SNPs selected for replication in replication studies combined by meta-analysis (replication), and of all studies combined by meta-analysis (all combined). P-values for log-additive association results (negative base 10 logarithm) are shown with recombination rates (cm/Mb) based on HapMap phase II data, and pairwise r² and superimposed D' values are displayed at the bottom for all SNPs included in the GWAS analysis. Coordinates refer to genome build 36.1. Panel A depicts the region of 2p21 including the EPAS1 gene region (46,353,240 – 46,498,984). Panel B depicts the region of 11q13 (68,852,465 – 69,037,945). Panel C depicts the region of 12q24.31 including the SCARB1 gene region (123,800,267 – 124,008,657).

Figure 2. Forest plots for three SNPs achieving genome-wide significance in RCC GWAS

Forest plots show stratified odds ratios (OR) for SNPs selected for replication and achieving genome-wide significance. The two highly correlated SNPs located at 2p21, rs7579899 and rs11894252, gave very similar results in stratified analysis, and only the results of one of the SNPs (rs11894252) are shown in the figure. Apart from the odds ratios for heterozygous and homozygous, odds ratios and 95% confidence intervals were estimated by the per rare allele log-additive trend model. All models were adjusted for sex, study and country. The overall log-additive OR is shown by the broken vertical line. P-values indicate heterogeneity for OR within each group.