Does Bilirubin Have a Causal Relationship With Vitiligo? A Mendelian Randomization Study and Bioinformatics Analysis

Danfeng Xu,1 Yinmeng Yin,2 Yan Teng,1 Youming Huang,1 Yong Yu,1 Xiaohua Tao,1 Yibin Fan,1 Xiaoxia Ding1 1Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Dermatology, Haining Central Hospital, Haining, Zhejiang, People’s Republic of ChinaCorrespondence: Yibin Fan; Xiaoxia Ding, Email [email protected]; [email protected]: Vitiligo is a complex acquired pigmentary disorder whose pathogenesis is closely linked to oxidative stress. Although bilirubin, a potent endogenous antioxidant, has been implicated in various dermatological conditions, its specific role in vitiligo remains poorly defined. This study aims to investigate the causal associations between bilirubin and vitiligo using Mendelian randomization (MR) analysis, complemented by bioinformatics validation to unravel the underlying molecular mechanisms.Methods: Genome-wide association study (GWAS) data pertaining to vitiligo and bilirubin were obtained, followed by the execution of a bidirectional MR analysis. Additionally, we performed a bioinformatics analysis using microarray datasets to identify differentially expressed genes (DEGs) in relation to bilirubin in patients with vitiligo. Pathway enrichment and gene interaction networks were constructed to explore the molecular mechanisms linking bilirubin to vitiligo pathogenesis.Results: Forward MR analysis demonstrated a significant causal relationship between elevated levels of total bilirubin (P=0.038) and direct bilirubin (P=0.013) with reduced risk of vitiligo. In contrast, reverse MR analysis showed no significant causal effect of vitiligo on bilirubin (P> 0.05). Bioinformatics analyses identified 136 DEGs in generalized vitiligo, 32 in segmental vitiligo, and 9 in non-segmental vitiligo. Enrichment analysis highlighted significant associations with oxidative stress-related pathways, including PI3K-Akt and JAK-STAT signaling, which are critical in melanocyte survival and immune regulation.Conclusion: This study provides robust evidence supporting a causal relationship between elevated bilirubin and a reduced risk of vitiligo, driven by its antioxidant properties. The identified DEGs and enriched pathways further elucidate the molecular mechanisms of bilirubin in the pathogenesis of vitiligo through oxidative stress, and may provide insights for future therapeutic strategies.Keywords: vitiligo, bilirubin, Mendelian randomization, bioinformatics, oxidative stress