Causal relationship between folic acid and prostate cancer risk: Insights from Mendelian randomization analysis

Objective: Folic acid is a commonly used dietary supplement of trace element, but itmay increase the risk of prostate cancer (PCa). The aim of this study was to investigatethe causal relationship between PCa and folic acid supplementation, as well as dietaryfolate equivalents, using Mendelian randomization (MR) analysis. Methods: The Genome-Wide Association Study (GWAS) data of folic acidsupplementation and dietary folate equivalents were selected from UK Biobank.Meta-analysis of GWASs of PCa was obtained from PCa Association Group to InvestigateCancer-Associated Alterations in the Genome consortium. MR analysis was performedwith inverse variance weighted (IVW) method, MR-Egger regression, simple mode,weighted median, and weighted mode analysis. Heterogeneity and horizontal pleiotropytests and reverse MR analysis were conducted to assess the robustness and reliability ofthe causal inference. Results: Six single nucleotide polymorphisms (SNPs) associated with folic acidsupplementation and five SNPs associated with dietary folate equivalents were identifiedas instrumental variables. Genetically predicted folic acid supplementation wasassociated with an increased risk of PCa (OR 1.200,p<0.001, by IVW method), andthere was no evidence of heterogeneity, horizontal pleiotropy, or significant reversecausality (allp>0.05). In contrast, dietary folate equivalents showed no significantcorrelation with PCa (p>0.05 for all five MR methods). Conclusion: This study demonstrated an association between increased risk of PCaand folic acid supplementation, but not with dietary folate equivalents. These findingshave implications for public health interventions and personalized preventive strategiesfor PCa.