Genetically predicted levels of folate, vitamin B₁₂, and risk of autoimmune diseases: A Mendelian randomization study

Evidence from observational studies on the association of folate and vitamin B₁₂ with autoimmune diseases are conflicting.

We aimed to investigate the relationship of folate and vitamin B₁₂ with autoimmune diseases using Mendelian randomization (MR).

We selected single-nucleotide polymorphisms associated with folate and vitamin B₁₂ at the genome-wide significance level. Summary-level data for four common autoimmune diseases (vitiligo, inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus) were obtained from large-scale genome-wide association studies, with a sample size of 44,266, 86,640, 58,284, and 23,210, respectively. MR analyses were conducted using the inverse variance weighted (IVW) approach, and sensitivity analyses were further performed to test the robustness.

We found that a higher genetically determined serum folate level per one standard deviation (SD) was associated with a decreased risk of vitiligo by the IVW method [odds ratios (OR) = 0.47; 95% confidence interval (CI): 0.32-0.69; P = 1.33 × 10^-4]. Sensitivity analyses using alternative methods showed similar associations, and no evidence of pleiotropy was detected by MR-Egger regression (P = 0.919). In addition, we observed that vitamin B₁₂ per one SD was positively associated with IBD (IVW: OR = 1.14, 95% CI: 1.03-1.26, P = 0.010; maximum likelihood: OR = 1.14, 95% CI: 1.01-1.29, P = 0.035; MR-PRESSO: OR = 1.14, 95% CI:1.01-1.28, P =0.037), while the association was not significant after Bonferroni correction.

The study provides convincing evidence for an inverse association between serum folate level and risk of vitiligo. Further studies are warranted to elucidate the possible association between vitamin B₁₂ and risk of IBD.