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Previous observational studies have suggested that gut microbiota might be associated with vitiligo. However, owing to the limitations in observational studies of reverse causality and confounders, it remains unclear that whether and how the causal relationships exist. The results suggested that pylum.Bacteroidetes, family.BacteroidalesS24.7, genus.LachnospiraceaeND3007, genus.Marvinbryantia are protective factors for vitiligo. Conversely, family.Lachnospiraceae, order.Burkholderiales, genus.Adlercreutzia, genus.Catenibacterium and genus.Lachnospira are risk factors for vitiligo. In addition, the causative connection between dietary factors and the gut microbiota associated with vitiligo was also investigated. The results revealed that 'alcohol intake versus 10 years pervious' results in a reduction in the abundance of genus.Lachnospiraceae ND3007 and family.BacteroidalesS24.7, bread intake leads to a reduction of genus.Marvinbryantia, 'average weekly red wine intake' is linked to a decrease in the abundance of order.Burkholderiales, tea intake is associated with an augmentation in the abundance of genus.Catenibacterium, salad/raw vegetable intake elevates the abundance of order.Burkholderiales. In summary, this Mendelian randomization study substantiates potential causal effects of gut microbiota on vitiligo. Modulating the gut microbiota through regulating dietary composition may be a novel strategy for preventing vitiligo., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The specific role of oxidative stress (OS) in vitiligo and alopecia areata (AA) remains unclear. The aim of this study was to analyze and identify the key markers of OS in vitiligo and AA by bioinformatics., Methods: We obtained vitiligo and AA datasets from gene expression omnibus (GEO) database. The difference-expressed genes of vitiligo and AA were identified by differential analysis, and the functions of difference-expressed genes were identified by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) enrichment analysis. Subsequently, Veen package was used to obtain the intersection genes of OS-related genes with vitiligo and AA. Finally, we used CIBERSORT to assess the infiltration of immune cells in vitiligo and AA., Results: Through enrichment analysis, we found that vitiligo and AA were mainly enriched in cell cycle and cell adhesion molecular channels. We identified KLB and EIF3C as key genes in OS regulation of vitiligo and AA, and found that KLB and EIF3C participate in disease progression by regulating T cells and neutrophils., Conclusions: According to our findings, KLB and EIF3C play a crucial role in the progression and development of vitiligo and AA, which have been identified as biomarkers and target for early diagnosis of patients., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Vitiligo is an autoimmune disease involving loss of melanocytes. Although several genetic studies have confirmed that genetic factors play an important role, its pathogenesis remains incompletely characterized. In this study, a genome-wide meta-analysis was conducted to search for more susceptibility variants of vitiligo. Tang et al performed a GWAS for cohort I (1117 vitiligo cases and 1701 healthy controls) previously, and we conducted a GWAS for cohort II (3323 vitiligo cases and 7186 healthy controls) in this study, with the results subjected to a genome-wide meta-analysis and linkage disequilibrium analysis. We identify, to our knowledge, 11 previously unreported susceptibility variants, of which 6 variants are located in the intronic regions, and the remaining 5 variants are located within intergenic regions between genes. In addition, the results of polygenic risk score show that the best evaluated effect for target data is among significant SNVs of the base data. The susceptibility genes of vitiligo are mainly enriched in the immune-related functions and pathways. The susceptibility variants expand the role of genetic factors associated with vitiligo. The bioinformatics analysis for risk genes provides further insight into the pathogenesis of vitiligo., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Recent studies increasingly suggest that microbial infections and the immune responses they elicit play significant roles in the pathogenesis of chronic inflammatory skin diseases. This study uses Mendelian randomization (MR) and Bayesian weighted Mendelian randomization (BWMR) to explore the causal relationships between immune antibody responses and four common skin diseases: psoriasis, atopic dermatitis (AD), rosacea, and vitiligo., Methods: We utilized summary statistics from genome-wide association studies (GWAS) for antibody responses to 13 infectious pathogens and four skin diseases. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) to assess causal relationships using multiple MR methods, including inverse variance weighted (IVW), MR Egger, and weighted median. BWMR was also employed to confirm findings and address potential pleiotropy., Results: The IVW analysis identified significant associations between specific antibody responses and the skin diseases studied. Key findings include protective associations of anti-Epstein-Barr virus (EBV) IgG seropositivity and Helicobacter pylori UREA antibody levels with psoriasis and AD. anti-chlamydia trachomatis IgG seropositivity, anti-polyomavirus 2 IgG seropositivity, and varicella zoster virus glycoprotein E and I antibody levels were negatively associated with rosacea, while EBV Elevated levels of the early antigen (EA-D) antibody levels and HHV-6 IE1B antibody levels were positively associated with rosacea. H. pylori Catalase antibody levels were protectively associated with vitiligo, whereas anti-herpes simplex virus 2 (HSV-2) IgG seropositivity was positively associated with vitiligo. The BWMR analysis confirmed these associations., Conclusion: This study underscores the significant role of H. pylori and other pathogens in these skin diseases, suggesting both protective and exacerbating effects depending on the specific condition. Understanding these pathogen-immune interactions can lead to the development of more effective, personalized treatments and preventative strategies, ultimately improving patient outcomes and quality of life., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: Vitiligo is an auto-immune progressive depigmentation disorder of the skin due to loss of melanocytes. Genetic risk is one of the important factors for development of vitiligo. Preponderance of vitiligo in certain ethnicities is known which can be analysed by understanding the distribution of allele frequencies across normal populations. Earlier GWAS identified 108 risk alleles for vitiligo in Europeans and East Asians. In this study, 64 of these risk alleles were used for analysing their enrichment and depletion across populations (1000 Genomes Project and IndiGen) with reference to 1000 Genomes dataset. Genetic risk scores were calculated and Fisher's exact test was performed to understand statistical significance of their variation in each population with respect to 1000 Genomes dataset as reference. In addition to SNPs reported in GWAS, significant variation in allele frequencies of 1079 vitiligo-related genes were also analysed. Two-tailed Chi-square test and Bonferroni's multiple adjustment values along with fixation index (≥ 0.5) and minimum allele frequency (≥ 0.05) were calculated and used to prioritise the variants based on pairwise comparison across populations., Results: Risk alleles rs1043101 and rs10768122 belong to 3 prime UTR of glutamate receptor gene SLC1A2 are found to be highly enriched in the South Asian population when compared with the 'global normal' population. Intron variant rs4766578 (ATXN2) was found to be deleted in SAS, EAS and AFR and enriched in EUR and AMR1. This risk allele is found to be under positive selection in SAS, AMR1 and EUR. From the ancillary vitiligo gene list, nonsynonymous variant rs16891982 was found to be enriched in the European and the Admixed American populations and depleted in all others. rs2279238 and rs11039155 belonging to the LXR-α gene involved in regulation of metalloproteinase 2 and 9 (melanocyte precursors) were found to be associated with vitiligo in the North Indian population (in earlier study)., Conclusion: The differential enrichment/depletion profile of the risk alleles provides insight into the underlying inter-population variations. This would provide clues towards prioritisation of SNPs associated with vitiligo thereby elucidating its preponderance in different ethnic groups., (© 2024. The Author(s).)

Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported. Multiomics analysis yields 235 candidate genes outside the MHC-region and the findings highlight the importance of genes involved in T-cell regulation. A rare 5'-UTR variant (rs781745126-T, MAF = 0.13% in Iceland) in LAG3 has the largest effect (OR = 3.42, P = 2.2 × 10 -16 ) and generates a novel start codon for an open reading frame upstream of the canonical protein translation initiation site. rs781745126-T reduces mRNA and surface expression of the inhibitory immune checkpoint LAG-3 co-receptor on activated lymphocyte subsets and halves LAG-3 levels in plasma among heterozygotes. All three homozygous carriers of rs781745126-T have AITD, of whom one also has two other T-cell mediated diseases, that is vitiligo and type 1 diabetes. rs781745126-T associates nominally with vitiligo (OR = 5.1, P = 6.5 × 10 -3 ) but not with type 1 diabetes. Thus, the effect of rs781745126-T is akin to drugs that inhibit LAG-3, which unleash immune responses and can have thyroid dysfunction and vitiligo as adverse events. This illustrates how a multiomics approach can reveal potential drug targets and safety concerns., (© 2024. The Author(s).)

Exosome-derived microRNAs (miRNAs) are biomacromolecules and nanoscale extracellular vesicles originating from intracellular compartments that are secreted by most cells into the extracellular space. This review examines the formation and function of exosomal miRNAs in biological information transfer, explores the pathogenesis of vitiligo, and highlights the relationship between exosomal miRNAs and vitiligo. The aim is to deepen the understanding of how exosomal miRNAs influence immune imbalance, oxidative stress damage, melanocyte-keratinocyte interactions, and melanogenesis disorders in the development of vitiligo. This enhanced understanding may contribute to the development of potential diagnostic and therapeutic options for vitiligo., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 li, Pang, He, Song, Xie, Zeng and Guo.)

Backgroud: Previous observational studies have shown that vitiligo usually co-manifests with a variety of dysglycemic diseases, such as Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM). Mendelian randomization (MR) analysis was performed to further evaluate the causal association between fasting plasma glucose, glycosylated hemoglobin (HbA1c), T1DM, T2DM and vitiligo., Materials and Methods: We used aggregated genome-wide association data from the Integrative Epidemiology Unit (IEU) online database of European adults vitiligo; HbA1c data were from IEU. Fasting blood glucose data were obtained from the European Bioinformatics Institute (EBI). T1DM and T2DM data were from FinnGen. We used bidirectional two-sample and multivariate MR analyses to test whether dysglycemic measures (fasting blood glucose, HbA1c), diabetes-related measures (T1DM, T2DM) are causatively associated with vitiligo. Inverse variance weighting (IVW) method was used as the main test method, MR-Egger, Weighted mode and Weighted median were used as supplementary methods., Results: We found no statistically significant evidence to support a causal association between dysglycemic traits and vitiligo, but in the correlation analysis of diabetic traits, our data supported a positive causal association between T1DM and vitiligo (p = 0.018). In the follow-up multivariate MR analysis, our results still supported this conclusion (p = 0.016), and suggested that HbA1c was not a mediator of T1DM affecting the pathogenesis of vitiligo. No reverse causality was found in any of the reverse MR Analyses of dysglycemic traits and diabetic traits., Conclusions: Our findings support that T1DM is a risk factor for the development of vitiligo, and this conclusion may explain why the co-presentation of T1DM and vitiligo is often seen in observational studies. Clinical use of measures related to T1DM may be a new idea for the prevention or treatment of vitiligo., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Generalized vitiligo(GV) is a skin depigmenting condition due to loss of melanocytes. Regulatory T cells(Tregs), responsible for peripheral tolerance, show altered numbers and functions in GV patients, likely influenced by the aging process. Therefore, the present study was focused on measuring the relative telomere length of Tregs in 96 GV patients and 90 controls by qPCR, along with correlation of relative telomere length with in vitro Treg suppressive capacity. Interestingly, we found significantly decreased relative telomere length in Tregs of GV patients as compared to controls(p = 0.0001). Additionally, age based-analysis suggested significant decrease in relative telomere length in elderly GV patients(>40 years) in comparison to young GV patients(0-20 years; p = 0.0027). Furthermore, age of onset analysis suggested for reduced relative telomere length in early onset GV patients (0-20 years) in comparison to late onset GV patients(>40 years; p = 0.0036). The correlation analysis suggested positive correlation for relative telomere length with in vitro Tregs suppressive capacity(r = 0.68 & r = 0.45; p < 0.0001). Additionally, the in vitro Tregs suppressive capacity was significantly reduced in elderly GV patients(p = 0.003) and early onset GV patients(p = 0.0074). Overall, our study for the first time demonstrated that, the Tregs ageing due to telomere shortening may be responsible for altered Treg functions and number., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Background: Both psoriasis and vitiligo are autoimmune skin diseases. Previous observational studies have indicated a relationship between the two conditions, and simultaneous onset of both diseases poses increased health risks to patients. However, limited research has explored the causal relationship between psoriasis and vitiligo., Objectives: To investigate whether a causal association exists between psoriasis and vitiligo., Methods: A case of Chinese patients diagnosed with psoriasis and vitiligo has been reported. Transcriptome sequencing was performed on normal, psoriasis, vitiligo, and co-morbid skin tissues of the patients, and single-cell transcriptome sequencing was conducted on the co-morbid skin tissues. A comprehensive Mendelian randomization analysis of Genome-wide association studies (GWAS) was performed on a cohort of 261 018 European individuals with psoriasis from the IEU Open GWAS Project and vitiligo from the National Institutes of Health (NIH) Database of Genotypes and Phenotypes., Results: Case report and transcriptome results showed that skin tissue with vitiligo combined with psoriasis exhibited both vitiligo and psoriasis. Single-cell transcriptome sequencing results showed that in comparison to normal skin and psoriatic skin, the proportions of CD8+ T cells, natural killer cells, naive T cells, T helper cells 17, regulatory T cells, conventional type 1 dendritic cells, Conventional type 2 dendritic cells, and plasmacytoid dendritic cells were all increased in skin tissue with vitiligo combined with psoriasis. Mendelian randomization analysis included 4510 patients with psoriasis and 4680 patients with vitiligo. The results showed no causal relationship between vitiligo and psoriasis in the forward direction (p = 0.192; odds ratio [OR], 1.059; 95% confidence interval [CI], 0.971-1.155) or in the reverse direction (p = 0.459; OR, 0.927; 95% CI, 0.757-1.134)., Conclusions: This study suggests that the association between psoriasis and vitiligo may be closely related to immunity, however, Mendelian randomization studies do not support a causal relationship. These findings hold significant implications for clinicians aiming to enhance their understanding and treatment approaches for psoriasis and vitiligo., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: Tryptophan metabolism dysregulation has been observed in vitiligo. However, drawing a mechanistic linkage between this metabolic disturbance and vitiligo pathogenesis remains challenging., Objective: Aim to reveal the characterization of tryptophan metabolism in vitiligo and investigate the role of tryptophan metabolites in vitiligo pathophysiology., Methods: LC-MS/MS, dual-luciferase reporter assay, ELISA, qRT-PCR, small interfering RNA, western blotting, and immunohistochemistry were employed., Results: Kynurenine pathway activation and KYAT enzyme-associated deviation to kynurenic acid (KYNA) in the plasma of stable non-segmental vitiligo were determined. Using a public microarray dataset, we next validated the activation of kynurenine pathway was related with inflammatory-related genes expression in skin of vitiligo patients. Furthermore, we found that KYNA induced CXCL10 upregulation in keratinocytes via AhR activation. Moreover, the total activity of AhR agonist was increased while the AhR concentration per se was decreased in the plasma of vitiligo patients. Finally, higher KYAT, CXCL10, CYP1A1 and lower AhR expression in vitiligo lesional skin were observed by immunohistochemistry staining., Conclusion: This study depicts the metabolic and genetic characterizations of tryptophan metabolism in vitiligo and proposes that KYNA, a tryptophan-derived AhR ligand, can enhance CXCL10 expression in keratinocytes., (Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Although observational studies have suggested a correlation between vitiligo and rheumatic diseases, conclusive evidence supporting a causal relationship is still lacking. Therefore, this study aims to explore the potential causal relationship between vitiligo and rheumatic diseases., Methods: Using genome-wide association studies, we performed a two-sample Mendelian randomization (MR) analysis. In our analysis, the random-effects inverse variance weighted (IVW) method was predominantly employed, followed by several sensitivity analyses, which include heterogeneity, horizontal pleiotropy, outliers, and "leave-one-out" analyses., Results: The genetically predicted vitiligo was associated with an increased risk of rheumatoid arthritis (RA) (OR, 1.47; 95% confidence interval [CI], 1.29-1.68; p < 0.001), and systemic lupus erythematosus (SLE) (OR, 1.22; 95% CI, 1.06-1.39; p = 0.005). The causal associations were supported by sensitivity analyses. In Sjögren's syndrome and ankylosing spondylitis, no causal relationship with vitiligo was found in the study., Conclusion: Our MR results support the causal effect that vitiligo leads to a higher risk of RA and SLE. Individuals with vitiligo should be vigilant for the potential development of RA and SLE. Managing and addressing this potential requires regular monitoring., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: The pathogenesis of vitiligo remains elusive. Emerging evidence suggests that vitiligo is an immune-mediated disorder, in which a plethora of immune cells play pivotal roles. However, the association between circulating immune cells and vitiligo continues to be enigmatic., Materials and Methods: We extracted single nucleotide polymorphisms (SNPs) associated with immune circulating cells at a genome-wide significance level from the BLOOD CELL CONSORTIUM's genome-wide association study (GWAS) dataset. Summary data for 385,801 cases of vitiligo were obtained from a large-scale Finnish genome-wide association study (ncases=292, ncontrols=385,509). The inverse variance weighted (IVW) method was employed as the primary analytical approach for Mendelian randomization (MR) analysis. Additionally, heterogeneity was assessed using Cochran's Q value, and horizontal pleiotropy was evaluated using MR-Egger Mendelian Randomization Pleiotropy RESidual Sum and Outlier and leave-one-out analyses., Results: The risk of vitiligo was found to increase with the elevation of 4 circulating immune cells, as evidenced by the odds ratios (ORs) and 95% confidence intervals (CIs): basophils (OR=1.81; 95% CI: 1.01-3.24, p=0.0450), monocytes (OR=1.67; 95% CI: 1.23-2.26, p=0.0009), eosinophils (OR=1.78; 95% CI: 1.22-2.59, p=0.0028), and neutrophils (OR=1.65; 95% CI: 1.08-2.54, p=0.0208). After removing outliers, the sensitivity analysis of the above indicators did not show heterogeneity and pleiotropy., Conclusion: Our findings illuminate the association between circulating immune cells and vitiligo, offering insights that could guide clinical practices in the treatment of vitiligo., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xin, Yuan and Wang.)

Background: Vitiligo is a skin disorder with melanocyte destruction caused by complex interplay between multiple genetic and environmental factors. Recent studies have suggested DNA methylation is involved in the melanocyte damage, but the underlying mechanism remains unknown., Objective: To explore the abnormal DNA methylation patterns in vitiligo lesional and nonlesional skin, and the mechanism of DNA methylation involved in vitiligo pathogenesis., Methods: Initially, the genome-wide aberrant DNA methylation profiles in lesional and nonlesional skin of vitiligo were detect via Illumina methylation EPIC 850k Beadchip. Subsequently, a comprehensive analysis was conduct to investigate the genomic characteristics of differentially methylated regions (DMRs). Furthermore, the effects of key aberrant methylated genes on cell apoptosis and function of both melanocytes and keratinocytes were further identified and validated by western bloting, ELISA, and immunofluorescence., Results: Compared with nonlesional skins, we discovered 79 significantly differentially methylated CpG sites in vitiligo lesions. These DMRs were mainly located in the gene body and the TS1500 region. Annexin A2 receptor (ANXA2R), a crucial gene in cell apoptosis, was hypermethylated in vitiligo lesions. Furthermore, we showed that ANXA2R displayed hypermethylation and low expression levels in both keratinocytes and melanocytes of vitiligo patients, and the hypermethylated-triggered downregulation of ANXA2R under oxidative stress induced melanocyte apoptosis, and inhibited the secretion of stem cell factor (SCF) from keratinocytes thus impaired the survival of melanocytes., Conclusions: Our study illustrates the DNA methylation modification in vitiligo, and further demonstrates the molecular mechanism of hypermethylated ANXA2R in the dysfunction of melanocytes under oxidative stress., (Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Vitiligo is an acquired autoimmune depigmented disorder characterized by the presence of white and well-defined patches on the skin, mucous membrane, or both. It is associated with a significant disease burden and has a profoundly impacts patients' quality of life. Autoimmune thyroid diseases (AITDs) result from an autoimmune system dysregulation, leading to an erroneous immune attack on the thyroid gland. Previous observational and epidemiological studies have suggested the association between vitiligo and AITDs. However, the bidirectional cause-effect relationship between vitiligo and AITDs has not been formally assessed., Method: Two-sample bidirectional Mendelian randomization (MR) analysis was conducted to explore potential causal relationships between genetically increased risk of vitiligo and AITDs, using summary statistics from genome-wide association studies in European populations. Causal effects were primarily estimated using the inverse variance weighted method, and additional quality control was performed using the MR-Egger, weighted median, simple mode, and weight mode methods. Sensitivity analysis was conducted to assess the robustness of the results., Results: The forward MR analysis showed a positive causal relationship between vitiligo and autoimmune thyroiditis (AIT), autoimmune hyperthyroidism (AIH), and Graves' disease (GD). The odds ratio (OR) were 1.17 (95% CI, 1.01-1.35; p = 0.04), 1.12 (95% CI, 1.03-1.22; p = 0.01), and 1.13 (95% CI, 1.06-1.20; p < 0.01), respectively. In the reverse MR analysis, a positive causal relationship was found between AIT and vitiligo, with an OR of 1.10 (95% CI, 1.01-1.35; p = 0.04). However, no causal relationship was observed between AIH (p = 0.10) or GD (p = 0.61) and vitiligo. Sensitivity analysis revealed no evidence of horizontal pleiotropy or heterogeneity., Conclusions: The genetic-level investigation provides evidence of a genetic causal association between susceptibility to vitiligo and an increased risk of AITDs. Additionally, the results demonstrate a genetic causal association between susceptibility to AIT and an increased risk of vitiligo, while not indicating a similar association with susceptibility to AIH or GD., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Objective: This study employed Mendelian Randomization (MR) to investigate the causal relationship between genetic susceptibility to vitiligo and the risk of various autoimmune diseases, along with the mediating role of blood metabolites., Methods: We performed two-sample MR analyses using aggregated genome-wide association studies (GWAS) data on 486 blood metabolites, vitiligo, and nine autoimmune diseases to investigate blood metabolites' causal effects on the susceptibility of vitiligo and the associations of vitiligo with nine autoimmune comorbidities. We also applied multivariable MR to unravel metabolites by which vitiligo influences the pathogenesis of autoimmune diseases., Results: Our findings indicate that vitiligo amplified the risk of several autoimmune diseases, including rheumatoid arthritis (OR 1.17; 95 % CI 1.08-1.27), psoriasis (OR 1.10; 95 % CI 1.04-1.17), type 1 diabetes (OR 1.41; 95 % CI 1.23-1.63), pernicious anemia (OR 1.23; 95 % CI 1.12-1.36), autoimmune hypothyroidism (OR 1.19; 95 % CI 1.11-1.26), alopecia areata (OR 1.22; 95 % CI 1.10-1.35), and autoimmune Addison's disease (OR 1.22; 95 % CI 1.12-1.33). Additionally, our analysis identified correlations with vitiligo for 14 known (nine risk, five protective) and seven uncharacterized serum metabolites. After adjusting for genetically predicted levels of histidine and pyruvate, the associations between vitiligo and these diseases were attenuated., Conclusions: We substantiated vitiligo's influence on susceptibility to seven autoimmune diseases and conducted a thorough investigation of serum metabolites correlated with vitiligo. Histidine and pyruvate are potential mediators of vitiligo associated with autoimmune diseases.By combining metabolomics with genomics, we provide new perspectives on the etiology of vitiligo and its immune comorbidities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Exploration of gene expression variations is a potential source to unravel biological pathways involved in pathological changes in body and understand the mechanism underneath. Vitiligo patients were explored for gene expression changes transcriptionally at perilesional site in comparison to normal site of same patients for melanogenesis pathway (TYR, DCT & TYRP1) cell adhesion (MMPs & TIMP1), cell survival (BCL2 & BAX1) as well as proliferation, migration & development (SOX9, SOX10 & MITF) regulatory system, using skin biopsy samples. Results were also compared with changes in gene expression for melanocytes under stress after hydrogen peroxide treatment in-vitro. Gene amplification was carried out via real time PCR. We found increased expression of proliferation, migration & development regulatory genes as well as melanogenesis pathway genes at perilesional site of patients. In-vitro study also supports induced MITF expression and disturbed melanogenesis in melanocytes under stress. Expression level ratio of cell survival regulatory genes' (BCL2/BAX1) as well as cell adhesion regulatory genes (MMPs/TIMP1) was observed upregulated at patient's perilesional site however downregulated in hydrogen peroxide treated melanocytes in-vitro. Observed upregulated gene expression at perilesional site of patients may be via positive feedback loop in response to stress to increase cell tolerance power to survive against adverse conditions. Gene expression analysis suggests better cell survival and proliferation potential at perilesional site in vitiligo patients. It seems in-vivo conditions/growth factors supports cells to fight for survival to accommodate stressed conditions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Vitiligo, as a common pigment defect in the skin, hair, and mucous membranes, results from the destruction of melanocytes. Recent investigations have shown that miRNA dysregulation contributes in the pathogenesis of vitiligo. Therefore, in this research, our aim is to explore the relationship between miR-202 rs12355840, miR-211 rs8039189, and miR-1238 rs12973308 polymorphisms and susceptibility to vitiligo. A total number of 136 vitiligo patients and 129 healthy individuals as a control group were included in this research. The salting out approach was implemented to extraction genomic DNA. The genetic polymorphisms of miR-202 rs12355840, miR-211 rs8039189, and miR-1238 rs12973308 were determined using PCR-RFLP approach. The findings revealed that miR-202 rs12355840 polymorphism under codominant (CT and TT genotypes), dominant, recessive, overdominant, and also allelic models is correlated with increased risk of vitiligo. In addition, codominant, dominant, overdominant, as well as allelic models of miR-211 rs8039189 polymorphism decrease risk of vitiligo. No significant relationship was observed between the miR-1238 rs12973308 polymorphism and susceptibility to vitiligo. The miR-211 rs8039189 polymorphism may serve a protective effect on vitiligo development and miR-202 rs12355840 polymorphism may act as a risk factor for vitiligo susceptibility., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Vitiligo is a skin disease characterized by selective loss of melanocytes, which seriously affects the appearance and causes great psychological stress to patients. In this study, we performed a comprehensive analysis of two vitiligo microarray datasets from the GEO database using bioinformatics tools to identify 297 up-regulated mRNAs and 186 down-regulated mRNAs, revealing important roles for pathways related to melanin synthesis, tyrosine metabolism, and inflammatory factors, such as "PPAR signaling pathway", "tyrosine metabolism", "nonalcoholic fatty liver disease (NAFLD) pathway", "melanogenesis", and "IL-17 signaling pathway". Combining the Search Tool for Interacting Chemicals (STITCH) database 5.0 and the drug-gene interaction database 3.0 (DGIdb), we identified that the PPAR-γ agonist rosiglitazone may promote melanin synthesis via EDNRB. Next, we investigated the mechanism of rosiglitazone and PPAR-γ pathway in promoting melanin production. Consistent with the results of bioinformatics analysis, the expression levels of PPAR-γ, EDNRB, and TYR were significantly reduced in human non-segmental vitiligo skin along with the reduction of MITF, a key gene for epidermal melanogenesis. Meanwhile, rosiglitazone increased melanin synthesis capacity in melanocytes and zebrafish by activating PPAR-γ and upregulating TYR, TYRP-1, and TYRP-2. Conversely, treatment of melanocytes with the PPAR-γ antagonist GW resulted in inhibition of melanin synthesis and expression of melanin-related factors. At the same time, simultaneous treatment of rosiglitazone with GW reversed the inhibitory effect of GW on melanin synthesis. In this study, we identified that rosiglitazone, an important insulin sensitizer, promotes melanin synthesis in melanocytes by increasing PPAR-γ activity and upregulating the expression levels of EDNRB and TYR. These findings may provide new ideas for exploring the pathogenesis and potential therapeutic targets of non-segmental vitiligo., (© 2023. The Author(s).)

Background: The pathogenesis of vitiligo remains unclear. The genes encoding vitiligo-related RNA-binding proteins (RBPs) and their underlying pathogenic mechanism have not been determined., Results: Single-cell transcriptome sequencing (scRNA-seq) data from the CNCB database was obtained to identify distinct cell types and subpopulations and the relative proportion changes in vitiligo and healthy samples. We identified 14 different cell types and 28 cell subpopulations. The proportion of each cell subpopulation significantly differed between the patients with vitiligo and healthy groups. Using RBP genes for unsupervised clustering, we obtained the specific RBP genes of different cell types in vitiligo and healthy groups. The RBP gene expression was highly heterogeneous; there were significant differences in some cell types, such as keratinocytes, Langerhans, and melanocytes, while there were no significant differences in other cells, such as T cells and fibroblasts, in the two groups. The melanocyte-specific RBP genes were enriched in the apoptosis and immune-related pathways in the patients with vitiligo. Combined with the bulk RNA-seq data of melanocytes, key RBP genes related to melanocytes were identified, including eight upregulated RBP genes (CDKN2A, HLA-A, RPL12, RPL29, RPL31, RPS19, RPS21, and RPS28) and one downregulated RBP gene (SLC3A2). Cell experiments were conducted to explore the role of the key RBP gene SLC3A2 in vitiligo. Cell experiments confirmed that melanocyte proliferation decreased, whereas apoptosis increased, after SLC3A2 knockdown. SLC3A2 knockdown in melanocytes also decreased the SOD activity and melanin content; increased the Fe 2+ , ROS, and MDA content; significantly increased the expression levels of TYR and COX2; and decreased the expression levels of glutathione and GPX4., Conclusion: We identified the RBP genes of different cell subsets in patients with vitiligo and confirmed that downregulating SLC3A2 can promote ferroptosis in melanocytes. These findings provide new insights into the pathogenesis of vitiligo., (© 2024. The Author(s).)

Objective: This study aims to identify causal variants associated with vitiligo in an expanded region of 10q22.1. Materials and Methods: We conducted a fine-scale deep analysis of the expanded 10q22.1 region using in a large genome-wide association studies dataset consisting of 1117 cases and 1701 controls through imputation. We selected five nominal coding single nucleotide polymorphisms (SNPs) located in SLC29A3 and CDH23 and genotyped them in an independent cohort of 2479 cases and 2451 controls in a Chinese Han population cohort using the Sequenom MassArray iPLEX1 system. Results: A missense SNP in SLC29A3 , rs2252996, showed strong evidence of association with vitiligo ( p  = 1.34 × 10 -8 , odds ratio [OR] = 0.82). Three synonymous SNPs (rs1084004 in SLC29A3 ; rs12218559 and rs10999978 in CDH23 ) provided suggestive evidence of association for vitiligo ( p  = 1.69 × 10 -6 , OR = 0.84; p  = 9.47 × 10 -5 , OR = 1.18; p  = 6.90 × 10 -4 , OR = 1.16, respectively). Stepwise conditional analyses identified two significant independent disease-associated signals from the four SNPs (both p  < 0.05; both D' = 0.03; and r 2  = 0.00). Conclusion: The study identifies four genetic coding variants in SLC29A3 and CDH23 on 10q22.1 that may contribute to vitiligo susceptibility with one missense variant affecting disease subphenotypes. The presence of multiple genetic variants underscores their significant role in the genetic pathogenesis of the disease.

Background: Tuberous sclerosis complex (TSC), an autosomal-dominant disorder, is characterized by hamartomas affecting multiple organ systems. The underlying etiology of TSC is the pathogenic variations of the TSC1 or TSC2 genes. The phenotype variability of TSC could lead to missed diagnosis; therefore, the latest molecular diagnostic criteria for identifying a heterozygous pathogenic variant in either the TSC1 or TSC2 gene filled this gap. Furthermore, the pathogenicity of numerous variants remains unverified, potentially leading to misinterpretations of their functional consequences., Methods: In this study, a single patient presenting with atypical vitiligo-like skin lesions suspected to have TSC was enrolled. Targeted next-generation sequencing and Sanger sequencing were employed to identify a pathogenic variant. Additionally, a minigene splicing assay was conducted to assess the impact of TSC1 c.1030-2A>T, located in intron 10, on RNA splicing., Results: A novel TSC1: c.1030-2A>T heterozygosis variant was identified in intron 10. In vitro minigene assay revealed that the c.1030-2A>T variant caused exon 11 skipping, resulting in a frameshift in the absence of 112 base pairs of mature messenger RNA and premature termination after 174 base pairs (p.Ala344Glnfs*59)., Conclusion: The detection of this novel pathogenic TSC1 variant in the patient with atypical vitiligo-like skin lesions enrolled in our study ultimately resulted in the diagnosis of TSC. As a result, our study contributes to expanding the mutational spectrum of the TSC1 gene and refining the genotype-phenotype map of TSC., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Objective: Vitiligo is a common systemic, idiopathic autoimmune disease. The aim of this study was to analyze the frequency of variants of the superoxide dismutase 1 (SOD1) gene (50 bp Ins/Del, rs4817415, rs2070424, rs1041740, rs17880135) and circulating plasma protein levels through in-silico analysis., Patients and Methods: Blood samples were collected from adult patients of both sexes with a clinical diagnosis of vitiligo. ELISA tests for SOD and analysis of gene variants by qPCR were compared to a disease-free reference group., Results: The population analyzed was young people between 29 and 37 years old, with a higher percentage of women. The population was found in the Hardy-Weinberg equilibrium (HWE). The 50 bp Ins/Del, rs4817415, and rs2070424 variants showed no significant difference between groups (p > 0.05). Although, in the dominant model, the CT and CTTT genotypes of the rs1041740 and rs17880135 variants showed an association with susceptibility to vitiligo compared to the control. Plasma SOD levels showed significant differences between the groups, and when stratified according to the genotypes of each variant, there was a significant difference, except with the rs17880135 variant. The haplotypes InsCGTC and InsAGCC are shown to be risk factors for susceptibility to vitiligo. The in-silico analysis demonstrated that the rs4817415, rs2070424, rs1041740, and rs17880135 variants of the SOD1 gene participate in the modification of selected regulatory elements for differentiating the protein, transcription factors, and long non-coding RNA., Conclusions: Information regarding the pathogenesis of vitiligo helps recognize risk factors and identify the relationship of diagnostic markers of cell damage inherent to the disease. This will help improve aspects of prevention and the choice of treatment alternatives appropriate to each case.

Vitiligo is a complex disease wherein the environmental factors, in conjunction with the underlying genetic predispositions, trigger the autoimmune destruction of melanocytes, ultimately leading to depigmented patches on the skin. While genetic factors have been extensively studied, the knowledge on environmental triggers remains sparse and less understood. To address this knowledge gap, we present the first comprehensive knowledgebase of vitiligo-triggering chemicals namely, Vitiligo-linked Chemical Exposome Knowledgebase (ViCEKb). ViCEKb involves an extensive and systematic manual effort in curation of published literature and subsequent compilation of 113 unique chemical triggers of vitiligo. ViCEKb standardizes various chemical information, and categorizes the chemicals based on their evidences and sources of exposure. Importantly, ViCEKb contains a wide range of metrics necessary for different toxicological evaluations. Notably, we observed that ViCEKb chemicals are present in a variety of consumer products. For instance, Propyl gallate is present as a fragrance substance in various household products, and Flutamide is used in medication to treat prostate cancer. These two chemicals have the highest level of evidence in ViCEKb, but are not regulated for their skin sensitizing effects. Furthermore, an extensive cheminformatics-based investigation revealed that ViCEKb chemical space is structurally diverse and comprises unique chemical scaffolds in comparison with skin specific regulatory lists. For example, Neomycin and 2,3,5-Triglycidyl-4-aminophenol have unique chemical scaffolds and the highest level of evidence in ViCEKb, but are not regulated for their skin sensitizing effects. Finally, a transcriptomics-based analysis of ViCEKb chemical perturbations in skin cell samples highlighted the commonality in their linked biological processes. Overall, we present the first comprehensive effort in compilation and exploration of various chemical triggers of vitiligo. We believe such a resource will enable in deciphering the complex etiology of vitiligo and aid in the characterization of human chemical exposome. ViCEKb is freely available for academic research at: https://cb.imsc.res.in/vicekb., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Several studies have emphasized the role of DNA methylation in vitiligo. However, its profile in human skin of individuals with vitiligo remains unknown. Here, we aimed to study the DNA methylation profile of vitiligo using pairwise comparisons of lesions, peri-lesions, and healthy skin. We investigated DNA methylation levels in six lesional skin, six peri-lesional skin, and eight healthy skin samples using an Illumina 850 K methylation chip. We then integrated DNA methylation data with transcriptome data to identify differentially methylated and expressed genes (DMEGs) and analyzed their functional enrichment. Subsequently, we compared the methylation and transcriptome characteristics of all skin samples, and the related genes were further studied using scRNA-seq data. Finally, validation was performed using an external dataset. We observed more DNA hypomethylated sites in patients with vitiligo. Further integrated analysis identified 264 DMEGs that were mainly functionally enriched in cell division, pigmentation, circadian rhythm, fatty acid metabolism, peroxidase activity, synapse regulation, and extracellular matrix. In addition, in the peri-lesional skin, we found that methylation levels of 102 DMEGs differed prior to changes in their transcription levels and identified 16 key pre-DMEGs (ANLN, CDCA3, CENPA, DEPDC1, ECT2, DEPDC1B, HMMR, KIF18A, KIF18B, TTK, KIF23, DCT, EDNRB, MITF, OCA2, and TYRP1). Single-cell RNA analysis showed that these genes were associated with cycling keratinocytes and melanocytes. Further analysis of cellular communication indicated the involvement of the extracellular matrix. The expression of related genes was verified using an external dataset. To the best of our knowledge, this is the first study to report a comprehensive DNA methylation profile of clinical vitiligo and peri-lesional skin. These findings would contribute to future research on the pathogenesis of vitiligo and potential therapeutic strategies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Plasma exosomal microRNAs (miRNAs) have been used as potential biomarkers for various diseases and have been investigated for their possible involvement in the pathogenesis of vitiligo. However, the miRNA expression profile of plasma exosomes in patients with non-segmental vitiligo (NSV) has not been determined yet., Objective: To screen differentially expressed microRNAs in plasma exosomes derived from patients with NSV and explore their roles in the pathogenesis of NSV., Methods: High-throughput sequencing was performed to determine the expression profiles of exosomal miRNAs in NSV. The effect of upregulated miR-1469 in NSV circulating exosomes on natural killer (NK) cells was further investigated using various molecular biological techniques., Results: MiR-1469 was identified as a candidate biomarker whose expression was significantly increased in circulating exosomes of NSV patients. Circulating exosomes were internalized by NK cells and increased NK cell proliferation viability and IFN-γ secretion capacity delivering miR-1469. Further studies revealed that the upregulation of CD122, the predicted target of miR-1469, could partially reverse the effect of miR-1469 on natural killer cells., Conclusion: Alterations in plasma exosomal cargo occur in NSV and appear to contribute to NK cell dysfunction. Exosomal miR-1469 may be a biomarker of disease activity and could be used as a therapeutic drug target against innate immunity in NSV patients. The present study provides new insights into the role of exosomal miRNAs in NSV and suggests a novel miR-1469-CD122-IFN-γ pathway of NK cell underlying pathogenesis of NSV., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Vitiligo is one of the common chronic autoimmune skin diseases in clinic, which is characterized by localized or generalized depigmentation and seriously affects the physical and mental health of patients. At present, the pathogenesis of vitiligo is not clear; mainly, heredity, autoimmunity, oxidative stress, melanocyte (MC) self-destruction, and the destruction, death, or dysfunction of MCs caused by various reasons are always the core of vitiligo. Regulatory cell death (RCD) is an active and orderly death mode of cells regulated by genes, which widely exists in various life activities, plays a pivotal role in maintaining the homeostasis of the organism, and is closely related to the occurrence and development of many diseases. With the deepening of the research and understanding of RCD, people gradually found that there are many different forms of RCD in the lesions and perilesional skin of vitiligo patients, such as apoptosis, autophagy, pyroptosis, ferroptosis, and so on. Different cell death modes have different mechanisms in vitiligo, and different RCDs can interact and regulate each other. In this article, the mechanism related to RCD in the pathogenesis of vitiligo is reviewed, which provides new ideas for exploring the pathogenesis and targeted treatment of vitiligo.

Background: Vitiligo is an acquired and progressive mucocutaneous disease with the damage of functioning epidermal melanocytes. Metabolic syndrome is associated with inflammatory skin diseases incorporating vitiligo. The circadian dysfunction triggers the pathogenesis of metabolic diseases, so our study aimed to determine the relationship between aryl hydrocarbon receptor nuclear translocator-like gene, a ligand-activated transcription factor and sensor of environmental chemicals, expression and polymorphism with non-segmental vitiligo, as well as its effect on lipid profile., Methods: This case-control study was handled on 50 non-segmental vitiligo patients (generalized (12) and localized type (focal; 24 and acrofacial; 14)) and 50 matched controls. Each subject was proposed for full history taking, clinical examinations, serum lipid profile, and measurement of BMAL1 gene expression in the blood, and BMAL1 rs2279287 polymorphism of DNA extract from whole blood by real time-PCR., Results: We identified that total cholesterol, triglyceride, and low-density lipoprotein were significantly higher, but high-density lipoprotein was significantly lower in non-segmental vitiligo patients than in the control group. A significant increase in circadian gene expression in non-segmental vitiligo patients was observed, with more detection of the BMAL1 T/C genotype (92%) than the T/T genotype. There was a significant positive relationship between the level of the circadian gene and the vitiligo patient's age, age of onset, and VIDA Score. The level of the circadian gene at Cutoff  ≥ 1.16 can predict the prognosis of vitiligo with a sensitivity of 78%, specificity of 84%, and accuracy of 81%., Conclusion: The circadian gene has an active role in the progress of non-segmental vitiligo and targeting this gene could have a significant impact on its management., (© 2024. The Author(s).)

The loss of epidermal melanocytes is a distinguishing feature of vitiligo (VIT), a prevalent and long-lasting skin ailment. While various hypotheses exist to explain the cause of VIT, the precise mechanisms leading to this disease remain unclear. Zinc finger MIZ-type containing 1 (ZMIZ1) has a strong link with the development and occurrence of VIT. However, the exact role of ZMIZ1 and its underlying mechanisms in VIT are not well understood. Our study aims to illustrate that targeting ZMIZ1 is an effective therapeutic and prophylactic strategy for treating VIT. We obtained the RNA expression profile of VIT samples using RNA-seq and determined the locations and expression of ZMIZ1 in these samples via immunochemistry. Glucose uptake was analyzed through immunofluorescence and glucose uptake assay. We evaluated mRNA levels using qPCR and used plasmids transfection to knock down ZMIZ1 in PIG1 and PIG3V cell lines. The activation of the mTOR/AKT/GSK-3β signalling pathway was assessed using Western blotting analysis. We found that ZMIZ1 expression was decreased in VIT samples. Decreased ZMIZ1 expression inhibits the proliferation, migration, and invasion of melanocytes in vitro. Moreover, we revealed that decreased ZMIZ1 could also inhibit the glucose uptake of melanocytes in vitro. Decreased ZMIZ1 expression inhibits the activation of the mTOR/AKT/GSK-3β pathway and the expression of melanin synthesis-related proteins in melanocytes. Finally, we demonstrated that decreased ZMIZ1 may inhibit the cell viability of melanocytes and the synthesis of melanin by mTOR/AKT/GSK-3β-mediated oxidative stress in vitro. In conclusion, our study suggests that decreased ZMIZ1 suppresses melanogenesis in vitiligo by regulating the mTOR/AKT/GSK-3β-mediated glucose uptake in vitro, making ZMIZ1 an attractive therapeutic target for the treatment of VIT., (© 2023. The Society for In Vitro Biology.)

Introduction: Vitiligo is a common depigmentation disorder characterized by defined white patches on the skin and affecting around 0.5% to 2% of the general population. Genetic association studies have identified several pre-disposing genes and single nucleotide polymorphisms (SNPs) for vitiligo pathogenesis; nonetheless, the reports are often conflicting and rarely conclusive. This comprehensive meta-analysis study was designed to evaluate the effect of the risk variants on vitiligo aetiology and covariate stratified vitiligo risk in the Asian population, considering all the studies published so far., Methods: We followed a systematic and comprehensive search to identify the relevant vitiligo-related candidate gene association studies in PubMed using specific keywords. After data extraction, we calculated, for the variants involved, the study-level unadjusted odds ratio, standard errors, and 95% confidence intervals by using logistic regression with additive, dominant effect, and recessive models using R software package (R, 3.4.2) "metafor." Subgroup analysis was performed using logistic regression (generalized linear model; "glm") of disease status on subgroup-specific genotype counts. For a better understanding of the likely biological function of vitiligo-associated variant obtained through the meta-analysis, in silico functional analyses, through standard publicly available web tools, were also conducted., Results: Thirty-one vitiligo-associated case-control studies on eleven SNPs were analysed in our study. In the fixed-effect meta-analysis, one variant upstream of TNF-α gene: rs1800629 was found to be associated with vitiligo risk in the additive (p = 4.26E-06), dominant (p = 1.65E-7), and recessive (p = 0.000453) models. After Benjamini-Hochberg false discovery rate (FDR) correction, rs1800629/TNF-α was found to be significant at 5% FDR in the dominant (padj = 1.82E-6) and recessive models (padj = 0.0049). In silico characterization revealed the prioritized variant to be regulatory in nature and thus having potential to contribute towards vitiligo pathogenesis., Conclusion: Our study constitutes the first comprehensive meta-analysis of candidate gene-based association studies reported in the whole of the Asian population, followed by an in silico analysis of the vitiligo-associated variant. According to the findings of our study, TNF-α single nucleotide variant rs1800629G&gt;A has a risk association, potentially contributing to vitiligo pathogenesis in the Asian population., (© 2024 S. Karger AG, Basel.)

Although a large number of existing studies have confirmed that people with vitiligo are prone to mental disorders, these observational studies may be subject to confounding factors and reverse causality, so the true causal relationship is inconclusive. We conducted a bidirectional Mendelian randomization (MR) analysis to assess the causality between vitiligo and mental disorders, namely depression, anxiety, insomnia, schizophrenia, bipolar disorder, obsessive-compulsive disorder (OCD) and attention-deficit hyperactivity disorder (ADHD). Summary statistics from large available genome-wide association study (GWAS) datasets for generalized vitiligo (n = 44 266), depression (n = 173 005), anxiety (n = 17 310), insomnia (n = 386 988), schizophrenia (n = 130 644), bipolar disorder (n = 413 466), OCD (n = 9725) and ADHD (n = 225 534) were utilized. Inverse-variance weighted (IVW), MR-Egger and weighted median were employed to estimate causal effects. Sensitivity analysis and MR Pleiotropy Residual Sum and Outliers (MR PRESSO) were conducted to assess heterogeneity and pleiotropy, ensuring the robustness of the results. Additionally, we corrected for estimating bias that might be brought on by sample overlap using MRlap. In our findings, none of the rigorous bidirectional MR analyses uncovered a significant causal association. Even after applying the MRlap correction, the effect sizes remained statistically nonsignificant, thereby reinforcing the conclusions drawn via IVW. In summary, our genetic-level investigation did not reveal a causal link between generalized vitiligo and mental disorders., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8 + T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases., (© 2023. The Author(s).)

Vitiligo is a chronic skin disorder characterised by the loss of melanocytes and subsequent skin depigmentation. Although many theories have been proposed in the literature, none alone explains the pathogenesis of vitiligo. Oxidative stress has been identified as a potential factor in the pathogenesis of vitiligo. A growing body of evidence suggests that antioxidant therapies may offer a promising approach to managing this condition. This review summarises the potential mechanisms of oxidative stress and the types of melanocyte death in vitiligo. We also provide a brief overview of the most commonly studied antioxidants. Melanocytes in vitiligo are thought to be damaged by an accumulation of reactive oxygen species to destroy the structural and functional integrity of their DNA, lipids, and proteins. Various causes, including exogenous and endogenous stress factors, an imbalance between prooxidants and antioxidants, disruption of antioxidant pathways, and gene polymorphisms, lead to the overproduction of reactive oxygen species. Although necroptosis, pyroptosis, ferroptosis, and oxeiptosis are newer types of cell death that may contribute to the pathophysiology of vitiligo, apoptosis remains the most studied cell death mechanism in vitiligo. According to studies, vitamin E helps to treat lipid peroxidation of the skin caused by psoralen ultra-violet A treatment. In addition, Polypodium leucotomos increased the efficacy of psoralen ultra-violet A or narrow-band ultraviolet B therapy. Our review provides valuable insights into the potential role of oxidative stress in pathogenesis and antioxidant-based supporting therapies in treating vitiligo, offering a promising avenue for further research and the development of effective treatment strategies., (© 2023. The Author(s).)

Background: Vitiligo has been correlated with an abnormal gut microbiota. We aimed to systematically identify characteristics of the gut microbial compositions, genetic functions, and potential metabolic features in patients with non-segmental vitiligo., Methods: Twenty-five patients with non-segmental vitiligo and 25 matched healthy controls (HCs) were enrolled. Metagenomic sequencing and bioinformatic analysis were performed to determine the gut microbiota profiles. Differences in gut microbiota diversity and composition between patients with vitiligo and HCs were analyzed. Gene functions and gut metabolic modules were predicted with the Kyoto Encyclopedia of Gene and Genomes (KEGG) and MetaCyc databases., Results: Compared with HCs, alpha diversity of intestinal microbiome in vitiligo patients was significantly reduced. At the species level, the relative abundance of Staphylococcus thermophiles was decreased, and that of Bacteroides fragilis was increased in patients with vitiligo compared with those of the HCs. Linear discriminant analysis (LDA) effect size (LEfSe) analysis revealed representative microbial markers of Lachnospiraceae&#95;bacterium&#95;BX3, Massilioclostridium&#95;coli, TM7&#95;phylum&#95;sp&#95;oral&#95;taxon&#95;348 and Bacteroides&#95;fragilis for patients with vitiligo. KEGG gene function analysis showed that the NOD-like receptor signaling pathway was significantly enriched in patients with vitiligo. Gut metabolic modules (GMMs) analysis showed that cysteine degradation was significantly down-regulated, and galactose degradation was up-regulated in patients with vitiligo. A panel of 28 microbial features was constructed to distinguish patients with vitiligo from HCs., Conclusions: The gut microbial profiles and genetic functions of patients with vitiligo were distinct from those of the HCs. The identified gut microbial markers may potentially be used for earlier diagnosis and treatment targets., (© 2023. BioMed Central Ltd., part of Springer Nature.)

This study aimed to identify the abnormal expression of long noncoding RNAs (lncRNAs) in T cells from patients with vitiligo and to investigate their functional roles in the immune system. Using microarray analysis, the expression levels of RNA transcripts in T cells from patients with vitiligo and controls were compared. We identified several genes and validated their expression levels in T cells from 41 vitiligo patients and 41 controls. The biological functions of the lncRNAs were studied in a transfection study using an RNA pull-down assay, followed by proteomic analysis and western blotting. The expression levels of 134 genes were significantly increased, and those of 142 genes were significantly decreased in T cells from vitiligo patients. After validation, six genes had increased expression, and three genes had decreased expression in T cells from patients with vitiligo. T-cell expression of LOC100506314 was increased in vitiligo, especially CD4+, but not CD8+ T cells. The expression levels of LOC100506314 in CD4+ T cells was positively and significantly associated with the severity of vitiligo. LOC100506314 was bound to the signal transducer and activator of transcription 3 (STAT3) and macrophage migration inhibitory factor (MIF). Enhanced expression of LOC100506314 inhibited the phosphorylation of STAT3, protein kinase B (AKT), and extracellular signal-regulated protein kinases (ERK), as well as the levels of nuclear protein of p65 and the expression of IL-6 and IL-17 in Jurkat cells and T cells from patients with vitiligo. In conclusion, this study showed that the expression of LOC100506314 was elevated in CD4+ T cells from patients with vitiligo and associated the severity of vitiligo. LOC100506314 interacted with STAT3 and MIF and inhibited IL-6 and IL-17 expression by suppressing the STAT3, nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κ B), AKT, and ERK pathways. Enhanced expression of LOC100506314 in T cells may be a potential treatment strategy for vitiligo., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ning-Sheng Lai et al.)

Generalized vitiligo (GV) is an autoimmune skin depigmenting disease characterized by loss of functional melanocytes. Nuclear factor of activated T cells (NFATs) play a key role in regulatory T cells' (Tregs) activation and function. Our previous studies have highlighted the role of reduced NFATs expression and activity in impaired Tregs suppressive capacity, leading to GV pathogenesis. 3'UTR region and structural single nucleotide polymorphisms(SNPs) could lead to reduced NFAT expression and activity. Therefore, we studied the association of NFATs 3'UTR [NFATC2 rs4811198 (T > G) & NFATC4 rs11848279 (A > G)] and structural [NFATC1 rs754093 (T > G) & NFATC2 rs12479626 (T > C)] SNPs in 427 GV patients and 415 controls from Gujarat population by Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). Additionally, we carried out genotype-phenotype correlation and in silico analysis to assess the effect of NFATs SNPs on NFATs expression and structure. NFATC2 rs4811198 (T > G) 3' UTR & NFATC2 rs12479626 (T > C) structural SNPs were significantly associated with GV (p < 0.0001). Interestingly, for NFATC2 rs4811198 (T > G) SNP, there was a significant difference in the TT vs GG genotypes' frequencies (p = 0.0034; Table 2), and for NFATC2 rs12479626 (T > C) SNP there was a significant difference between TT vs TC and CC genotypes' frequencies (p < 0.0001 & p = 0.0002) between GV patients and controls. Furthermore, Odds ratio suggested that the susceptible alleles for NFATC2 rs4811198 (T > G) & NFATC2 rs12479626 (T > C) SNPs increased the risk of GV by 1.38 & 3.04 fold. However, the NFAT 3' UTR [NFATC2 rs4811198 (T > G)] and structural [NFATC1 rs754093 (T > G)] SNPs were not significantly associated with GV. Interestingly, the genotype-phenotype correlation suggested that the susceptible 'G' allele of NFATC2 rs4811198 (T > G) & NFATC4 rs11848279 (A > G) 3' UTR SNPs lead to reduced NFATC2 and NFATC4 expression (p < 0.0001). Furthermore, in silico analysis suggested that hsa-miR-3183 & hsa-miR-6720-3p miRNAs specifically bound to 'G' allele of NFATC2 rs4811198 SNP and has-miR-4652-3p miRNA specifically bound to 'G' allele of NFATC4 rs11848279 SNP. Overall, our study suggests that NFATC2 rs4811198 (T > G) 3' UTR & NFATC2 rs12479626 (T > C) structural SNPs may be associated with GV susceptibility in Gujarat population. Moreover, the susceptible alleles for the 3' UTR SNPs could lead to reduced NFATs levels, which may further possibly, affect the Treg suppressive function leading to GV., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Lymphocyte enhancer-binding factor-1 (LEF1) is responsible for melanocyte proliferation, migration and differentiation and its downregulation may result in depigmentation in vitiligo. Narrowband UVB (NB-UVB) phototherapy is known to enhance melanocyte migration from hair follicles to lesional epidermis; hence, it may have a role in the upregulation of LEF1., Objectives: We intended to assess the expression of LEF1 both before and after NB-UVB therapy and correlate it with the extent of re-pigmentation., Materials and Methods: In this prospective cohort study, 30 patients of unstable non-segmental vitiligo were administered NB-UVB phototherapy for 24 weeks. Skin biopsies were obtained from acral and non-acral sites in all patients, both prior to initiation and after completion of phototherapy and LEF1 expression was measured., Results: Amongst the 16 patients who completed the study, at 24 weeks, all patients achieved > 50% re-pigmentation. However, > 75% re-pigmentation was achieved in only 11.1% of acral patches, whereas it was achieved in a significantly higher number of non-acral patches (66.6%) (p = 0.05). A significant increase was observed in the mean fluorescent intensity of the LEF1 gene in both acral as well as non-acral areas at 24 weeks as compared to baseline (p = 0.0078), However, no difference was observed between acral and non-acral lesions in the LEF1 expression at 24 weeks or the change in LEF1 expression from baseline., Conclusion: LEF1 expression modulates the re-pigmentation of vitiligo lesions after treatment with NBUVB phototherapy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Vitiligo is an autoimmune depigmentation dermatosis induced by melanocyte destruction, and CD8 + T cells play a pivotal role in melanocyte destruction. However, an accurate profile of the CD8 + T cell receptor (TCR) repertoire in vitiligo patients has not been reported, and the clonotype features of the involved CD8 + T cells remain largely unknown. This study aimed to assess the TCRβ chain repertoire diversity and composition of blood in nine nonsegmental vitiligo patients via high-throughput sequencing. Vitiligo patients manifested a low TCRβ repertoire diversity with highly expanded clones. Differential usage of TRBV, the TRBJ gene, and the TRBV/TRBJ combination were compared between patients with vitiligo and healthy controls. A set of TRBV/TRBJ combinations could differentiate patients with vitiligo from healthy controls (area under the curve = 0.9383, 95% CI: 0.8167-1.00). Our study revealed distinct TCRβ repertoires of CD8 + T cells in patients with vitiligo and will help explore novel immune biomarkers and potential therapeutic targets for vitiligo., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Vitiligo is an acquired, autoimmune, depigmented skin disease with unclear pathogenesis. Mitochondrial dysfunction contributes significantly to vitiligo, and mitophagy is vital for removing damaged mitochondria. Herein, using bioinformatic analysis, we sought to determine the possible role of mitophagy-associated genes in vitiligo and immune infiltration., Methods: Microarrays GSE53146 and GSE75819 were used to identify differentially expressed genes (DEGs) in vitiligo. By crossing vitiligo DEGs with mitophagy-related genes, the mitophagy-related DEGs were identified. Functional enrichment and protein-protein intersection (PPI) analyses were conducted. Then, the hub genes were identified using two machine algorithms, and receiver operating characteristic (ROC) curves were generated. Next, the immune infiltration and its connection with hub genes in vitiligo were investigated. Finally, the Regnetwork database and NetworkAnalyst were used to predict the upstream transcriptional factors (TFs), microRNAs (miRNAs), and the protein-compound network., Results: A total of 24 mitophagy-related genes were screened. Then, five mitophagy hub genes ( GABARAPL2 , SP1 , USP8 , RELA , and TBC1D17 ) were identified using two machine learning algorithms, and these genes showed high diagnostic specificity for vitiligo. The PPI network showed that hub genes interacted with each other. The mRNA expression levels of five hub genes were validated in vitiligo lesions by qRT-PCR and were compatible with the bioinformatic results. Compared with controls, the abundance of activated CD4 + T cells, CD8 + T cells, immature dendritic cells and B cells, myeloid-derived suppressor cells (MDSCs), gamma delta T cells, mast cells, regulatory T cells (Tregs), and T helper 2 (Th2) cells was higher. However, the abundance of CD56 bright natural killer (NK) cells, monocytes, and NK cells was lower. Correlation analysis revealed a link between hub genes and immune infiltration. Meanwhile, we predicted the upstream TFs and miRNAs and the target compounds of hub genes., Conclusion: Five hub mitophagy-related genes were identified and correlated with immune infiltration in vitiligo. These findings suggested that mitophagy may promote the development of vitiligo by activating immune infiltration. Our study might enhance our comprehension of the pathogenic mechanism of vitiligo and offer a treatment option for vitiligo., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luo, Zhu, Guo and Li.)

Vitiligo is an autoimmune complex pigmentation disease characterized by non-pigmented patches on the surface of the skin that affect approximately 0.5-2% population worldwide. The exact etiology is still unknown; however, vitiligo is hypothesized to be a multifactorial and genetically heterogeneous condition. Therefore, the current study is designed to investigate the anthropometric presentation and genetic spectrum of vitiligo in fifteen consanguineous Pakistani families. The clinical evaluation of participating individuals revealed varying degrees of disease severity, with 23 years as the average age of disease onset. The majority of the affected individuals had non-segmental vitiligo (NSV). Whole exome sequencing analysis revealed clustering of rare variants of known vitiligo-associated genes. For instance, in the affected individuals of family VF-12, we identified three novel rare variants of PTPN22 (c.1108C>A), NRROS (c.197C>T) and HERC2 (c.10969G>A) genes. All three variants replaced evolutionarily conserved amino acid residues in encoded proteins, which are predicted to impact the ionic interactions in the secondary structure. Although various in silico algorithms predicted low effect sizes for these variants individually, the clustering of them in affected individuals increases the polygenic burden of risk alleles. To our knowledge, this is the first study that highlights the complex etiology of vitiligo and genetic heterogeneity in multiplex consanguineous Pakistani families.

Background: The management of vitiligo is challenging due to limited treatment options, and therapeutic strategy varies according to the active or stable stage of vitiligo. PDE4 inhibitor has been used to treat various skin diseases, but the efficacy in vitiligo treatment is mixed., Objective: In this study, we aimed to investigate whether roflumilast, a PDE4 inhibitor, induces melanogenesis and attenuates oxidative stress-triggered damage in melanocytes, and if so, what is the mechanism., Methods: Melanin content assay, qRT-PCR, western blotting, ELISA, immunofluorescence assays, immunohistochemistry, small interfering RNA, flow cytometry, and transmission electron microscopy were employed., Results: Our results demonstrated that roflumilast alone only slightly increased melanogenesis, however, the combination of roflumilast and forskolin could boost cAMP levels, hence promoting melanogenesis more significantly. Moreover, roflumilast attenuated H 2 O 2 -induced apoptosis and mitochondrial morphological changes in melanocytes by reducing ROS levels. Furthermore, roflumilast activated AhR/Nrf2 pathway via cAMP whereas AhR silencing blocked roflumilast-induced Nrf2 nuclear translocation and reversed the inhibitory effect of roflumilast on H 2 O 2 -induced ROS production. Finally, we observed that the lesional skin of active vitiligo patients exhibited higher PDE4 expression levels., Conclusion: roflumilast enhances the melanogenesis effect of forskolin and protects melanocytes from H 2 O 2 -induced apoptosis by cAMP/AhR/Nrf2-activated ROS inhibition, highlighting its therapeutic potential in vitiligo treatment., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare.., (Copyright © 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Psoriasis and vitiligo are both chronic, skin-specific diseases classified as autoimmune diseases due to the involvement of several biochemical pathways in their pathogenesis, similar to those altered in other autoimmune diseases. The role of miRNAs in regulating skin autoimmune function has yet to be fully characterized., Aim: The aim of this study was to assess the expression profile of a panel of 11 circulating immune-related miRNAs in patients with autoimmune skin diseases, specifically psoriasis and vitiligo, and correlate their expression signature with the clinicopathological features of the diseases., Subjects and Methods: Relative gene expression quantification for 11 immune-related circulating miRNAs in plasma was done for 300 subjects-100 patients with psoriasis, 100 patients with vitiligo and 100 normal healthy volunteers-followed by different modalities of bioinformatics analysis for the results., Results: The expression levels of all the studied immune-related miRNAs were elevated in both autoimmune skin disorders, with much higher levels of expression in psoriasis than in vitiligo patients. There was a significant correlation between most of the studied miRNAs, suggesting shared target genes and/or pathways. Moreover, all the studied miRNAs showed significant results as biomarkers for autoimmune skin disease, with miRNA-145 being the best candidate. Regarding the clinicopathological data, miRNA-7, miRNA-9, miRNA-145, miRNA-148a, and miRNA-148b were positively correlated with age. All the miRNAs were inversely correlated with obesity and disease duration., Conclusion: This study highlights the critical role of miRNAs in skin-specific autoimmune diseases that proved to be potential biomarkers for autoimmune skin disorders, warranting their exploration as therapeutic targets., (© 2023. The Author(s).)

Background and Objectives : Vitiligo is a chronic autoimmune and depigmentation disorder in humans that manifests as whitening lesions. Reactive oxygen species (ROS) are involved in cell damage. Catalase (CAT) is a well-known oxidative stress regulator and is primarily responsible for the catalytic decomposition of hydrogen peroxide into water and oxygen. Based on previous case-control and meta-analysis studies, we assessed the prevalence of three single-nucleotide polymorphisms (SNPs) of the CAT genes A-89T (rs7943316), C389T (rs769217) and C419T (rs11032709) in participants with vitiligo and healthy controls in the Saudi population. Materials and Methods : We recruited 152 participants with vitiligo and 159 healthy controls for A-89T, C389T, and C419T SNP genotyping studies using PCR and RFLP analysis. Additionally, we performed linkage disequilibrium and haplotype analyses between vitiligo cases and controls. Results : The rs7943316 and rs11032709 SNPs of the CAT genes showed a positive association with vitiligo for both heterozygous genotypes and dominant genetic models (TT + AT vs. AA in A-89T and TT + CT vs. CC in C389T), in the CAT gene. Linkage disequilibrium analysis revealed a moderate linkage between rs7943316 and rs11032709 SNPs in vitiligo cases and controls. Haplotype frequency estimation revealed a significant association ( p = 0.003) among the three SNP alleles. Conclusions : The rs7943316 and rs11032709 SNPs of the CAT genes were strongly associated with susceptibility to vitiligo.

Vitiligo is acquired depigmentation due to multiple factors. Vitamin D in skin, through its receptors (VDR), regulates cell growth, differentiation, immune response and exerts both stimulatory and protective effects on melanocytes. The gene sequence encoding VDR has polymorphic forms such as ApaI and TaqI that may affect vitamin D actions. Narrowband ultraviolet B (NB-UVB) phototherapy became the mainstay of vitiligo treatment because of its efficacy and little side effects. The current work aimed at evaluating the possible association between VDR gene polymorphisms (TaqI and ApaI) and susceptibility of vitiligo and if they could be predictors of response to NB-UVB phototherapy in Egyptian vitiligo patients. 100 vitiligo patients indicated for NB-UVB phototherapy and 100 healthy age and sex matched controls were included. All participants were subjected to history taking, general and dermatological examinations, and VDR ApaI and TaqI gene polymorphisms analysis by PCR-RFLP. The patients received NB-UVB 3times per week for 6 months then revaluated. There was significant increase in Aa genotype of ApaI polymorphism in patients associated with significant increase in vitiligo activity. 66% of patient showed variable degrees of response to NB-UVB. The responders significantly had AA genotype of ApaI polymorphism. TaqI polymorphism showed nonsignificant effects on vitiligo susceptibility and response to NB-UVB. A allele of ApaI was significant independent predictor of NB-UVB phototherapy responders. VDR gene polymorphism (ApaI) may share in vitiligo pathogenesis and response to NB-UVB. Knowing the genetic background of the patient helps individualization of treatment to get better results., (© 2022. The Author(s).)

Vitiligo is the most common depigmenting disease characterized by achromic macules due to selective loss of melanocytes. The pathogenesis remains poorly elucidated, and multiple hypotheses exist regarding its pathogenesis. Evidence suggests that stress on melanocytes can result in activation of the immune system, and involvement of both activated cluster of differentiation (CD8+) cytotoxic and CD4+ T cells in the dysfunction, depigmentation, and apoptosis of melanocytes. Recent studies show that the interleukin 17 (IL-17) axis plays a central role in the pathogenesis of the disease. IL-17 is an important regulatory effector cytokine in this pathway. The aim of this study was to evaluate the association of IL-17A rs4711998 (-832A/G), IL-17A rs2275913 (-197G/A), and IL-17F rs763780 (7488A/G) with vitiligo in a Northeastern Mexican population. This was a case-control study and included 116 patients with vitiligo and 116 control subjects. Genotype characterization of IL-17A rs4711998 (-832A/G), IL-17A rs2275913 (-197G/A), and IL-17F rs763780 (7488A/G) was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. A p ≤ 0.05 was considered significant. It was observed that the combination of the genotypes GG/GA for IL-17F rs763780 (7488A/G) was associated with an increased risk for the development of vitiligo (OR 2.0943, 95% Cl 1.2375-3.5445, p = 0.0056). Regarding IL-17A rs4711998 (-832A/G) and IL-17A rs2275913 (-197G/A) genotyping, no association with vitiligo development was found. In conclusion, the SNP rs763780 in the IL-17F gene appears to be a risk factor for vitiligo development in this Mexican population and it may be useful in future studies, especially for the development of new therapies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)