Vitamin A compounds including retinol are thought to play a protective role in human carcinogenesis. However, recent studies have shown that men with higher serum retinol concentrations are at increased risk of both overall and aggressive prostate cancer, the most common cancer in men within developed populations. The biological mechanism underlying this association remains unclear. In the present investigation, we examined the associations between common genetic variants related to serum retinol status and prostate cancer risk in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) Consortium. The analysis includes 38,868 cases and 25,210 controls from 35 participating PRACTICAL studies. A Mendelian randomization approach was used to examine the individual association between 135 vitamin A-related single nucleotide polymorphisms (SNPs) and risk of overall prostate cancer. Logistical regression was used to estimate the odds ratio (OR) and confidence interval (CI) for the per allele association between each SNP and risk. Associations were examined using both genotyped and imputed data, and results for the latter are presented here based on their substantial similarity. In addition to examining SNPs demonstrating nominal significance (alpha < 0.05), a Bonferroni cut-point of < 0.0003 was used to adjust for multiple comparisons. Seven SNPs were found to be nominally significant at the p < 0.05 level; however, none remained significant after Bonferroni correction. Of these, five SNPs (rs4799751, OR = 0.97; rs9963553, OR= 1.03; rs9967180, OR=1.03; rs2167689, OR= 0.98; rs1941356, OR= 0.98) are located in or near three genes: transthyretin gene (TTR), trafficking protein particle complex 8 (TRAPPC8), and beta-1,4-galactosyltransferase 6 (B4GALT6). The carrier protein transthyretin is the only gene known to be related to retinol status based on prior GWAS analyses, while B4GALT6 encodes type-II membrane-bound glycoproteins which may be used as a potential cancer biomarker. The two other SNPs, rs1377189 (OR=0.96) and rs117053512 (OR=0.97), are located in desmoglein 3 (DSG3), whose encoded protein plays a role in maintenance of tissue architecture which may be upregulated in malignancies. Our large-scale Mendelian randomization analysis reveals some evidence of a relatively weak association between genetic variants related to vitamin A status and prostate cancer risk. These associations should be further examined in aggressive and fatal cancers.

Citation Format: Shakira M. Nelson, Tracy M. Layne, Stephanie J. Weinstein, Eric Karlins, Stephen J. Chanock, Demetrius Albanes, PRACTICAL Consortium. Prostate cancer risk and vitamin a related genetic variants in the PRACTICAL Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1272. doi:10.1158/1538-7445.AM2017-1272