Genetic Insights into the Potential Causal Role of LIPA and LTA4H in Vitiligo: A Single-Cell Integrative Analysis.
- 1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
Abstract
Zhen Zhang, Hong LuDepartment of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Hong Lu, Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Erqi District, Zhengzhou City, Henan Province, 450052, People’s Republic of China, Email [email protected]: Vitiligo is a complex autoimmune skin disorder characterized by the loss of melanocytes, imposing a significant psychosocial and economic burden on affected individuals. Despite the identification of numerous susceptibility loci through GWAS, translating these findings into clinical insights remains challenging as the cell-type-specific causal genes and their regulatory mechanisms are largely unexplored. Identifying these specific drivers is crucial for developing targeted precision therapies.Methods: We employed an integrative framework combining single-cell eQTL data and vitiligo GWAS summary statistics to identify cell-type-specific causal genes. Potential causal relationships were evaluated using two-sample Mendelian randomization (MR) and Bayesian colocalization analysis. Functional significance was explored via GO/KEGG enrichment. Finally, the prioritized candidates were validated using PBMC scRNA-seq dataset.Results: MR analysis identified several cell-type-specific causal transcripts. Beyond the established HLA-DRB1 in NK recruiting cells (β=1.84, pfdr< 0.001), two novel protective factors were prioritized: LIPA in monocytes (β=− 0.20, pfdr=0.02) and LTA4H in dendritic cells (β=− 0.44, pfdr=0.02). Bayesian colocalization (PPH4 > 0.7) confirmed shared causal variants at these loci. Functional enrichment highlighted lysosomal metabolism and antigen presentation. External validation (GSE231794) confirmed that HLA-DRB1 was significantly up-regulated in patient NK recruiting cells, while LIPA and LTA4H expression were markedly diminished in patients, aligning consistently with our genetic estimates.Conclusion: This study provides genetic insights into the potential involvement of LIPA and LTA4H in vitiligo. These findings suggest that a deficiency in these metabolic-immune regulators within specific myeloid subsets may contribute to the disease’s pathogenesis, highlighting them as potential targets for further functional investigation and precision intervention. Future studies should focus on in vivo and in vitro functional validation of these genes to further elucidate their precise roles in melanocyte stability and their potential as therapeutic targets for precision intervention.Keywords: vitiligo, single-cell eQTL, Mendelian randomization, LIPA, LTA4H, autoimmune metabolism
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BibTeX
@article{zhang2026genetic,
title = {{Genetic Insights into the Potential Causal Role of LIPA and LTA4H in Vitiligo: A Single-Cell Integrative Analysis.}},
author = {Zhen Zhang and Hong Lu},
journal = {Clinical, cosmetic and investigational dermatology},
year = {2026},
month = oct,
doi = {10.2147/ccid.s604033},
url = {https://europepmc.org/article/MED/42953151},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Genetic Insights into the Potential Causal Role of LIPA and LTA4H in Vitiligo: A Single-Cell Integrative Analysis.
AU - Zhen Zhang
AU - Hong Lu
PY - 2026
DA - 2026/10/23
JO - Clinical, cosmetic and investigational dermatology
DO - 10.2147/ccid.s604033
UR - https://europepmc.org/article/MED/42953151
AB - Zhen Zhang, Hong LuDepartment of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Hong Lu, Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Erqi District, Zhengzhou City, Henan Province, 450052, People’s Republic of China, Email [email protected]: Vitiligo is a complex autoimmune skin disorder characterized by the loss of melanocytes, imposing a significant psychosocial and economic burden on affected individuals. Despite the identification of numerous susceptibility loci through GWAS, translating these findings into clinical insights remains challenging as the cell-type-specific causal genes and their regulatory mechanisms are largely unexplored. Identifying these specific drivers is crucial for developing targeted precision therapies.Methods: We employed an integrative framework combining single-cell eQTL data and vitiligo GWAS summary statistics to identify cell-type-specific causal genes. Potential causal relationships were evaluated using two-sample Mendelian randomization (MR) and Bayesian colocalization analysis. Functional significance was explored via GO/KEGG enrichment. Finally, the prioritized candidates were validated using PBMC scRNA-seq dataset.Results: MR analysis identified several cell-type-specific causal transcripts. Beyond the established HLA-DRB1 in NK recruiting cells (β=1.84, pfdr< 0.001), two novel protective factors were prioritized: LIPA in monocytes (β=− 0.20, pfdr=0.02) and LTA4H in dendritic cells (β=− 0.44, pfdr=0.02). Bayesian colocalization (PPH4 > 0.7) confirmed shared causal variants at these loci. Functional enrichment highlighted lysosomal metabolism and antigen presentation. External validation (GSE231794) confirmed that HLA-DRB1 was significantly up-regulated in patient NK recruiting cells, while LIPA and LTA4H expression were markedly diminished in patients, aligning consistently with our genetic estimates.Conclusion: This study provides genetic insights into the potential involvement of LIPA and LTA4H in vitiligo. These findings suggest that a deficiency in these metabolic-immune regulators within specific myeloid subsets may contribute to the disease’s pathogenesis, highlighting them as potential targets for further functional investigation and precision intervention. Future studies should focus on in vivo and in vitro functional validation of these genes to further elucidate their precise roles in melanocyte stability and their potential as therapeutic targets for precision intervention.Keywords: vitiligo, single-cell eQTL, Mendelian randomization, LIPA, LTA4H, autoimmune metabolism
SN - 1178-7015
ER -