Interactions of SNPs in Folate Metabolism Related Genes on Prostate Cancer Aggressiveness in European Americans and African Americans

SIMPLE SUMMARY: Prostate cancer (PCa) is a complex disease. Identifying inherited genetic variants or single nucleotide polymorphisms (SNPs) for predicting PCa aggressiveness is essential for improving PCa clinical outcomes. However, the interactions of folate-related SNPs associated with PCa aggressiveness are understudied. The study’s objective is to evaluate interactions among the DHFR 19-bp polymorphism and 10 SNPs in folate metabolism and the one-carbon metabolism pathway associated with PCa aggressiveness. We evaluated 1294 PCa patients, including 690 European Americans (EAs) and 604 African Americans (AAs). None of the 11 individual polymorphisms were significant for EAs and AAs. For the EA PCa patients, the two SNP–SNP interaction pairs in MTHFR-MTHFD1 and MTHFR-SLC4A5 were significantly associated with aggressive PCa. For the AA PCa patients, the interaction of DHFR-19bp polymorphism and rs4652 (LGALS3) was significantly associated with aggressive PCa. These findings can provide valuable information for precision intervention and medicine of PCa aggressiveness. ABSTRACT: Background: Studies showed that folate and related single nucleotide polymorphisms (SNPs) could predict prostate cancer (PCa) risk. However, little is known about the interactions of folate-related SNPs associated with PCa aggressiveness. The study’s objective is to evaluate SNP–SNP interactions among the DHFR 19-bp polymorphism and 10 SNPs in folate metabolism and the one-carbon metabolism pathway associated with PCa aggressiveness. Methods: We evaluated 1294 PCa patients, including 690 European Americans (EAs) and 604 African Americans (AAs). Both individual SNP effects and pairwise SNP–SNP interactions were analyzed. Results: None of the 11 individual polymorphisms were significant for EAs and AAs. Three SNP–SNP interaction pairs can predict PCa aggressiveness with a medium to large effect size. For the EA PCa patients, the interaction between rs1801133 (MTHFR) and rs2236225 (MTHFD1), and rs1801131 (MTHFR) and rs7587117 (SLC4A5) were significantly associated with aggressive PCa. For the AA PCa patients, the interaction of DHFR-19bp polymorphism and rs4652 (LGALS3) was significantly associated with aggressive PCa. Conclusions: These SNP–SNP interactions in the folate metabolism-related genes have a larger impact than SNP individual effects on tumor aggressiveness for EA and AA PCa patients. These findings can provide valuable information for potential biological mechanisms of PCa aggressiveness.