Study Finds No Genetic Link Between Vitamin D Levels and Pemphigus Risk

The study, published in Clinical, Cosmetic and Investigational Dermatology, used a bidirectional two-sample Mendelian randomization (MR) approach to evaluate potential causal relationships. The findings indicate that neither low vitamin D levels contribute to pemphigus risk nor does pemphigus lead to altered vitamin D levels, challenging previous observational studies that suggested otherwise.

Pemphigus is a rare autoimmune disease characterized by the production of autoantibodies that attack the skin and mucous membranes. Given the role of vitamin D in regulating immune responses—particularly its influence on B-cell function—some earlier studies had speculated a protective effect of vitamin D against pemphigus. However, these observational studies were limited by potential confounding factors, making it unclear whether the relationship was truly causal.

To address this uncertainty, Yanchun Wang, College of Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi Province, People’s Republic of China, and colleagues applied Mendelian randomization techniques, which use genetic variants as proxies for modifiable exposures, helping to overcome issues of confounding and reverse causation. Data from genome-wide association studies (GWAS) were used to construct genetic instruments: 61 single nucleotide polymorphisms (SNPs) associated with serum vitamin D levels and 3 SNPs linked to pemphigus.

Key Findings:

• The study employed inverse variance weighting (IVW), weighted median, and MR-Egger regression to perform both forward and reverse Mendelian randomization (MR) analyses.
• The forward analysis found no significant causal effect of genetically predicted vitamin D levels on pemphigus risk (IVW OR = 0.835).
• The reverse analysis showed no evidence that pemphigus affected vitamin D levels (IVW OR = 1.000).
• The findings remained consistent across various sensitivity analyses.

To further validate the findings, the study tested for heterogeneity using the Cochran Q test and assessed horizontal pleiotropy through the MR-Egger intercept test. Both tests confirmed the reliability and robustness of the results, strengthening the conclusion that no causal relationship exists between vitamin D levels and pemphigus.

“These findings suggest that previously observed associations between vitamin D and pemphigus may be due to confounding factors rather than a direct causal link,” the authors noted. They emphasized the importance of cautious interpretation of observational studies and highlighted the need for further mechanistic research to explore other potential drivers of pemphigus pathogenesis.

"The study provides genetic evidence against a causal role for vitamin D in pemphigus, calling for future investigations using improved GWAS datasets and advanced analytical approaches to deepen understanding of this complex autoimmune disorder," the authors concluded.

Reference:

Wang Y, Cheng S, Que H. A Bidirectional Two-Sample Mendelian Randomization Study of Genetic Causality Between Vitamin D Levels and Pemphigus. Clin Cosmet Investig Dermatol. 2025;18:1167-1176. https://doi.org/10.2147/CCID.S523136