Clinical, cosmetic and investigational dermatology · 2026
Integrative Transcriptomic and Genetic Analysis Prioritizes SLC1A5 as a Programmed Cell Death-Associated Candidate Risk Gene in Vitiligo.
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Yao Jizhao, Chen Honghui, Zhou Xiulian, Hu Ting, Guo Hengshan, Ma Lili, Liu Minhong, Liu Fangyan, Zhang Ruiyang, Li Weiquan
Аннотация
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.
METHODS: Three GEO datasets (GSE65127, GSE53146, GSE75819) 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.
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 highlighted PARK7 and SLC1A5 as 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 linked SLC1A5 to glycosphingolipid biosynthesis and melanogenesis. Immune infiltration analysis showed elevated aDC, T helper, and Th2 cells but reduced NK CD56bright cells in vitiligo. SLC1A5 was significantly downregulated in vitiligo samples and demonstrated moderate diagnostic value.
CONCLUSION: This study identifies SLC1A5 as a genetically anchored PCD-associated gene potentially involved in vitiligo through metabolic reprogramming and immune modulation, and provides strong genetic evidence supporting SLC1A5 as a candidate for further mechanistic and translational investigation, while recognizing that functional studies are required before it can be considered a therapeutic target.
METHODS: Three GEO datasets (GSE65127, GSE53146, GSE75819) 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.
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 highlighted PARK7 and SLC1A5 as 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 linked SLC1A5 to glycosphingolipid biosynthesis and melanogenesis. Immune infiltration analysis showed elevated aDC, T helper, and Th2 cells but reduced NK CD56bright cells in vitiligo. SLC1A5 was significantly downregulated in vitiligo samples and demonstrated moderate diagnostic value.
CONCLUSION: This study identifies SLC1A5 as a genetically anchored PCD-associated gene potentially involved in vitiligo through metabolic reprogramming and immune modulation, and provides strong genetic evidence supporting SLC1A5 as a candidate for further mechanistic and translational investigation, while recognizing that functional studies are required before it can be considered a therapeutic target.