Identification of dietary factors that impact the gut microbiota associated with vitiligo: A Mendelian randomization study and meta-analysis.

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.

Antibody immune responses and causal relationships in four immune skin diseases: Evidence from Mendelian randomization and Bayesian Weighting (Antibody Responses in Skin Diseases: MR & Bayesian).

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.

Co-regulatory mechanisms and potential markers of oxidative stress-related genes in vitiligo and alopecia areata.

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.

The relationship between psoriasis and vitiligo: From a comprehensive study.

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.

Dysregulated tryptophan metabolism and AhR pathway contributed to CXCL10 upregulation in stable non-segmental vitiligo.

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.

Diabetes, glycemic profile and risk of vitiligo: A Mendelian randomization study.

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.

Exosome-derived microRNAs: emerging players in vitiligo.

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.

Identifying the genetic association between common rheumatic diseases and vitiligo.

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.

Estimation of genetic variation in vitiligo associated genes: Population genomics perspective.

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.

Start codon variant in LAG3 is associated with decreased LAG-3 expression and increased risk of autoimmune thyroid disease.

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.

Circulating immune cells and vitiligo: a bidirectional two-sample Mendelian randomization study.

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.

Roles of blood metabolites in mediating the relationship between vitiligo and autoimmune diseases: Evidence from a Mendelian randomization study.

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.

The causal relationship between vitiligo and autoimmune thyroid diseases: A bidirectional two-sample Mendelian randomization analysis.

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.

Oxidative stress-induced hypermethylation and low expression of ANXA2R: Novel insights into the dysfunction of melanocytes in vitiligo.

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.

Implication of regulatory T cells' telomere shortening in pathogenesis of generalized vitiligo.

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.

Association of SOD1 gene variants (50 bp Ins/Del, rs4817415, rs2070424, rs1041740, rs17880135) with plasma protein levels in vitiligo patients and their analysis in silico.

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.

Association between miR-202, miR-211, and miR-1238 gene polymorphisms and risk of vitiligo.

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.

Transcriptional variations at perilesional site in vitiligo patients: probably a fight for cell-survival.

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.

Identification of Coding Variants in 10q22.1 Associated with Vitiligo in the Chinese Han Population.

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 r2 = 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.