Causal Association of Folic Acid Supplementary Therapy and Gastric Ulcer: A Mendelian Randomization Study

Background. The incidence of gastric ulcer (GU) remains high worldwide with limited prevention. While promising animal experiments have suggested a potential preventive role of folic acid (FA) in the development of gastric ulcers, the lack of robust clinical evidence has hindered its widespread implementation as a preventative measure. Therefore, this research aims to determine the relationship between FA supplementation and GU genetically by Mendelian randomization (MR) approach, in order to establish a foundation for developing more effective preventative strategies for this condition. Methods. Genome-wide association studies (GWAS) investigating the association between folic acid or folate supplementation and gastric ulcers were sourced from the UK Biobank. The primary methods for Mendelian randomization analysis were the inverse variance-weighted (IVW) methods, including fixed-effect and random-effect IVW models. Other methods used to test the robustness of the results included simple model and median, weighted model and median, as well as penalized weighted median. Results. MR analysis was performed to investigate the causal effect of FA adjuvant therapy on GU. Seven single nucleotide polymorphisms (SNPs) of genetic loci associated with FA adjuvant therapy were identified. The random-effect and fixed-effect IVW models revealed that genetically predicted FA complementary therapy was significantly related to the reduction of GU risk (OR, 0.870; 95% CI, 0.826–0.917, p < 0.001; OR, 0.870; 95% CI, 0.825–0.918, p < 0.001). Similar results were also observed using simple mode (OR, 0.826; 95% CI, 0.724–0.943, p = 0.030), Weighted mode (OR, 0.828; 95% CI, 0.728–0.941, p = 0.028), simple median method (OR, 0.835; 95% CI, 0.773–0.901, p < 0.001), weighted median (OR, 0.854; 95% CI, 0.794–0.919, p < 0.001) and penalised weighted median (OR, 0.849; 95% CI, 0.789–0.914, p < 0.001). The association between FA supplementary therapy and GU was not considerably driven by any individual SNP according to the leave-one-out sensitivity analysis. Conclusions. This MR study provides evidence from a genetic perspective that FA supplementation may decrease the risk of gastric ulcer. Clinicians should prioritize the role of FA in preventing gastric ulcers among patients.