Causal Associations between Vitamin D Levels and Psoriasis, Atopic Dermatitis, and Vitiligo: A Bidirectional Two-Sample Mendelian Randomization Analysis.

BACKGROUND: Vitamin D level has been reported to be associated with psoriasis, atopic dermatitis, and vitiligo. However, its causal relationship with the risk of these three diseases remains unclear. METHODS: We obtained genome-wide association statistics for three measures of circulating vitamin D levels (25(OH)D in 120,618 individuals, and 25(OH)D3 and epimeric form C3-epi-25(OH)D3 in 40,562 individuals) and for the diseases psoriasis (3871 cases and 333,288 controls), atopic dermatitis (21,399 cases and 95,464 controls), and vitiligo (4680 cases and 39,586 controls). We performed Mendelian randomization using inverse-variance weighted, weighted median, MR-Egger, and MR-pleiotropy residual sum and outlier methods. We carried out sensitivity analyses to evaluate the robustness of the results. RESULTS: We showed that elevated vitamin D levels protected individuals from developing psoriasis (OR = 0.995, p = 8.84 × 10-4 for 25(OH)D; OR = 0.997, p = 1.81 × 10-3 for 25(OH)D3; and OR = 0.998, p = 0.044 for C3-epi-25(OH)D3). Genetically predicted risk of atopic dermatitis increased the levels of 25(OH)D (OR = 1.040, p = 7.14 × 10-4) and 25(OH)D3 (OR = 1.208, p = 0.048). A sensitivity analysis suggested the robustness of these causal associations. CONCLUSIONS: This study reported causal relationships between circulating vitamin D levels and the risk of psoriasis, atopic dermatitis, and vitiligo. These findings provide potential disease intervention and monitoring targets.

Genome-wide association analysis of anti-TNF-α treatment response in Chinese patients with psoriasis.

Background: TNF-α inhibitors are effective biological agents for treating psoriasis, but the treatment responses differ across patients. This study aimed to identify genetic biomarkers of anti-TNF-α response in Chinese psoriasis patients using a genome-wide association approach. Methods: We recruited two independent cohorts of Chinese psoriasis patients administered etanercept biosimilar (with or without methotrexate). We identified 61 and 87 good responders (PASI improvement ≥75%), 19 and 10 poor responders (PASI improvement <50%) after 24 weeks treatment in the two cohorts, respectively. Then we performed genome-wide association studies (GWAS) on anti-TNF-α response in each cohort independently, followed by a fixed-effects inverse-variance meta-analysis in the 148 good and 29 poor responders. Results: We tested genetic associations with >3 million genetic variants in either cohort. Meta-analysis identified significant associations within seven loci at p < 10-5, which also showed consistent association evidence in the two cohorts. These seven loci include rs2431355 (OR = 6.65, p = 4.46 × 10-7, IQGAP2-F2RL2 on 5q13.3), rs11801616 (OR = 0.11, p = 1.75 × 10-6, SDC3 on 1p35.2), rs3754679 (OR = 0.17, p = 7.71 × 10-6, CNOT11 on 2q11.2), rs13166823 (OR = 0.09, p = 3.71 × 10-6, IRF1-AS1 on 5q31.1), rs10220768 (OR = 5.49, p = 1.48 × 10-6, NPAP1 on 15q11.2), rs4796752 (OR = 5.56, p = 1.49 × 10-6, KRT31 on 17q21.2), and rs13045590 (OR = 0.08, p = 9.67 × 10-7, CTSZ on 20q13.3). Of the seven SNPs, six SNPs showed significant eQTL effect (p < 1 × 10-6) for several genes in multiple tissues. Conclusion: These results suggest novel biological mechanisms and potential biomarkers for the response to anti-TNF therapies. These findings warrant further validation.