Abstract PR-6: Variation in VDR pathway genes and renal cancer risk
Authors: Karami Sara , Brennan Paul , Phillip Rosenberg , Hung Rayjean , Purde Mark , Navratilova Marie , Mates Dana , Zaridze David , Idan Menashe , Janout Vladimir , Kollarova Helena , Bencko Vladimir , Matveev Vitaliy , Szesznia-Dabrowska Neonila , Holcatova Ivana , Yeager Marideth , Chanock Steven , Rothman Nat , Chow Wong-Ho , Boffetta Paolo , Moore Lee 
Published: May 2012

Abstract
PR-6
The conversion of vitamin D to its main biologically active form, 1,25-dihydroxy vitamin D, occurs in the kidney. Since the most biologically active form of vitamin D exerts its activity through binding to the intracellular vitamin D receptor (VDR), most studies of genetic susceptibility have primarily focused on variation within the VDR gene. But, the concert of genes that interact with VDR are vast; therefore, an analysis of genetic variation in VDR and other genes in its pathway may provide insight into the role of vitamin D in renal cell carcinoma (RCC) etiology. In this case-control study, we investigated the relationship between RCC risk and 139 single nucleotide polymorphisms (SNPs) in 8 target genes (VDR, RXRA, RXRB, CYP24A1, GC, STAT1, THRAP4 and TRAP5) of the expanded vitamin D pathway from subjects residing in Central and Eastern Europe. 1,097 RCC cases and 1,476 controls were recruited for this study where genomic DNA was analyzed using an Illumina Oligo Pool-All (OPA) assay. First, the minimum-p-value permutation (Min-P) test was used to identify genes that were associated with RCC risk and that remained significant at a cut off level of 10%. Next, a haplotype-based sliding window analysis of three consecutive SNPs was used to identify chromosome regions of interest that remained significant at a False Discovery Rate (FDR) of 10%. For these regions, haplotype relative risks were computed using the HaploStats package in R. Significant Min-P values were observed for two genes, which were selected for in-depth analysis: VDR (P-value: 0.024) and RXRA (P-value: 0.100). Two chromosomal regions of interest within the VDR gene were identified using the haplotype-based sliding window technique. The first region identified two haplotypes within intron 2, centered around rs4760648, that significantly increased RCC risk (haplotype 1: OR= 1.25; 95% CI= 1.04-1.50 and hapotype 2: OR= 1.26; 95% CI= 1.02-1.54) when compared to patients with the most common referent haplotype. The second signal identified a haplotype (rs886441 and rs12717991) located within intron 4 of the VDR gene that was associated with increased risk among participants with the TG (OR= 1.29; 95%CI= 1.08-1.54) haplotype compared to participants with most common referent haplotype, CA. The global p-values in R for these haplotypes were 0.025 and 0.028, respectively. Across the RXRA gene, a single haplotype located downstream, 3’ of the coding sequence, centered around rs3118523 was shown to increase RCC risk (OR= 1.41; 95% CI= 1.10-1.82) among individuals with the variant haplotype compared to those with the most common haplotype. This is the first study to our knowledge to comprehensively evaluate genetic variation in VDR and other pathway genes in relation to RCC risk. While replication and fine mapping studies will be required to confirm these findings, this study suggests that genes in the vitamin D pathway may modify RCC risk.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-6.