Integrative Transcriptomic and Genetic Analysis Prioritizesas a Programmed Cell Death-Associated Candidate Risk Gene in Vitiligo
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Background Programmed cell death (PCD) has been implicated in various autoimmune disorders, but its role in vitiligo remains poorly understood. This study aimed to identify PCD-related genes and elucidate their potential contribution to vitiligo pathogenesis through integrative bioinformatics analysis. s2001 Methods Three GEO datasets (,,) were merged to obtain a combined cohort of 40 controls and 30 vitiligo samples. Differentially expressed genes (DEGs) were identified using limma. GSVA was applied to assess 11 PCD pathways. Summary-data-based Mendelian randomization (SMR) and HEIDI testing integrated eQTL data with vitiligo to pinpoint causal genes. Bayesian colocalization and immune infiltration analyses were further performed. s2002 Results A total of 922 DEGs were identified, with pyroptosis and cuproptosis signatures upregulated in vitiligo whereas overall autophagy- and lysosome-dependent cell death–related gene expression was decreased. In contrast, pathway-level GSVA using a broader autophagy-related gene set indicated upregulated autophagy signaling, highlighting the context dependence of autophagy-related signatures. Overlapping DEGs with PCD gene sets yielded 75 differentially expressed PCD-related genes. SMR analysis prioritized 602 genes associated with vitiligo risk, and intersection with PCD genes highlightedandas key candidates. Bayesian colocalization analysis provided strong genetic support for SLC1A5 as a candidate gene, with lead SNP rs8105903 showing co
Abstract
Background Programmed cell death (PCD) has been implicated in various autoimmune disorders, but its role in vitiligo remains poorly understood. This study aimed to identify PCD-related genes and elucidate their potential contribution to vitiligo pathogenesis through integrative bioinformatics analysis. s2001 Methods Three GEO datasets (,,) were merged to obtain a combined cohort of 40 controls and 30 vitiligo samples. Differentially expressed genes (DEGs) were identified using limma. GSVA was applied to assess 11 PCD pathways. Summary-data-based Mendelian randomization (SMR) and HEIDI testing integrated eQTL data with vitiligo to pinpoint causal genes. Bayesian colocalization and immune infiltration analyses were further performed. s2002 Results A total of 922 DEGs were identified, with pyroptosis and cuproptosis signatures upregulated in vitiligo whereas overall autophagy- and lysosome-dependent cell death–related gene expression was decreased. In contrast, pathway-level GSVA using a broader autophagy-related gene set indicated upregulated autophagy signaling, highlighting the context dependence of autophagy-related signatures. Overlapping DEGs with PCD gene sets yielded 75 differentially expressed PCD-related genes. SMR analysis prioritized 602 genes associated with vitiligo risk, and intersection with PCD genes highlightedandas key candidates. Bayesian colocalization analysis provided strong genetic support for SLC1A5 as a candidate gene, with lead SNP rs8105903 showing consistent eQTL and GWAS signals. GSVA revealed downregulated melanogenesis and tyrosine metabolism alongside upregulated autophagy and NOD-like receptor signaling in vitiligo. Single-gene enrichment linkedto glycosphingolipid biosynthesis and melanogenesis. Immune infiltration analysis showed elevated aDC, T helper, and Th2 cells but reduced NK CD56bright cells in vitiligo.was significantly downregulated in vitiligo samples and demonstrated moderate diagnostic value. s2003 Conclusion This study identifiesas a genetically anchored PCD-associated gene potentially involved in vitiligo through metabolic reprogramming and immune modulation, and provides strong genetic evidence supportingas a candidate for further mechanistic and translational investigation, while recognizing that functional studies are required before it can be considered a therapeutic target. s2004