Alpha-tocopherol is a highly biologically active form of vitamin E that has been inconsistently associated with prostate cancer risk in cohorts and supplementation trials. In order to further elucidate the association using a Mendelian randomization approach that avoids sources of bias common in observational research, we examined genetic variants related to vitamin E status, including those from GWAS analyses of circulating vitamin E, in relation to prostate cancer risk in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) Consortium. The analysis included 38,868 cases and 25,210 controls from 35 participating cohorts and examined the association between 847 vitamin E-related single nucleotide polymorphisms (SNPs) in (or near) six genes and risk of prostate cancer. Logistical regression was used to estimate meta-analyzed case-control odds ratios (OR) and 95% confidence intervals (CI) for the per allele risk associations. Both genotyped and imputed data were examined, and results for the latter are presented based on the consistency between the two sets of findings. In addition to examining SNPs demonstrating nominal significance (alpha-error p<0.05), a Bonferroni threshold of <0.00006 was applied to adjust for multiple comparisons. We found 89 SNPs were nominally significantly associated with prostate cancer risk. This included SNPs involved in vitamin E transport (i.e., SEC14L2 and SCARB1) and metabolism (i.e., BUD13/ZNF259). The top three risk-associated SNPs (P <0.001) included rs141696823 (OR = 0.59, P=6.0x10-5) in CYP4F8 (cytochrome P450 family 4 subfamily F member 8) on 19p13.12 which functions as a prostaglandin hydroxylase in the seminal vesicles, and rs1915379 (OR = 1.04, P=0.0002) in CYP4F3 (cytochrome P450 family 4 subfamily F member 3) on 19p13.12 which oxidizes arachidonic acid and omega-hydroxylates tocopherol phytyl side chains, and has been directly associated with higher circulating alpha-tocopherol. The final SNP (r185614299, OR = 1.19, P=0.0004) is in NKAIN3 on 8q12.3, which encodes the Na+/K+ transporting ATPase Interacting Protein 3, a plasma membrane enzyme responsible for maintenance of intracellular electrolyte gradients. Vitamin E has been shown to reduce cell membrane lipid peroxidation, thereby promoting Na/K-ATPase activity. Other variants on this gene have previously been associated with serum alpha-tocopherol concentration in response to vitamin E supplementation in the ATBC Study. The present Mendelian randomization analysis suggests genetic variants related to vitamin E metabolism, its role as an antioxidant, and its function in inflammatory processes, may be associated with prostate cancer risk.

Citation Format: Tracy M. Layne, Shakira M. Nelson, Stephanie J. Weinstein, Eric Karlins, Stephen J. Chanock, Demetrius Albanes, The PRACTICAL Consortium. Vitamin E related genetic variants and prostate cancer risk: A Mendelian randomization analysis [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 1270. doi:10.1158/1538-7445.AM2017-1270