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Original paper

Evaluation of polymorphisms and expression of PTPN22, NLRP1 and TYR genes in vitiligo patients

Kaja Męcińska-Jundziłł
1
,
Tadeusz Tadrowski
1
,
Arkadiusz Jundziłł
2
,
Henryk Witmanowski
2
,
Rafał Czajkowki
1

  1. Department of Dermatology and Venerology, Faculty of Medicine in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland
  2. Department of Plastic, Reconstructive and Aesthetic Surgery, Faculty of Medicine in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland
Adv Dermatol Allergol 2023; XL (2): 225-233
Online publish date: 2023/03/30
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Introduction

Vitiligo is a pigmentary disorder associated with a selective loss of melanocytes leading to depigmentation of the skin, its appendages and mucous membranes. The incidence of the disease is 0.5–4% of the worldwide population [1]. Vitiligo is considered as an autoimmune/autoinflammatory disease developing in genetically predisposed patients [2]. Thanks to genome-wide association studies (GWAS) 50 different loci associated with vitiligo were identified [35]. About 85% of associated genes encode proteins involved in the functioning of the immune system and the process of apoptosis [6]. About half of these genes were identified in independent genetic studies of other autoimmune diseases [7].

The PTPN22 gene is located on chromosome 1 and it encodes the lymphoid-specific tyrosine phosphatase (LYP) [8, 9]. Many studies of the rs2476601 polymorphism showed its association with the higher risk of autoimmune diseases, such as vitiligo, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and autoimmune thyroid diseases [1013].

The NALP1 gene is located on chromosome 17 and it takes part in controlling of inflammation and apoptosis [1416]. There is an association between NALP1 gene polymorphisms and autoimmune diseases such as vitiligo, Addison’s disease, type 1 diabetes, celiac disease, systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis [1723].

The TYR gene is located on chromosome 11, it encodes tyrosinase recognized as the main autoantigen in vitiligo [24, 25].

Aim

The aim of the study was to evaluate the association between the rs2476601 polymorphism of the PTPN22 gene, the rs2670660 and rs6502867 polymorphisms of the NLRP1 gene and the rs1847134 and rs1393350 polymorphisms of the TYR gene and vitiligo. Other aims were to analyse the relationship between the polymorphisms of the investigated genes and their expression; to analyse the relationship between polymorphisms of the PTPN22 and NLRP1 genes and concomitant autoimmune diseases in vitiligo patients; to compare expression of PTPN22, NLRP1 and TYR genes in lesional and symmetrically non-lesional skin of vitiligo patients and in the healthy skin of the control group; and to analyse the relationship between expression of PTPN22, NLRP1 and TYR genes and clinical features as age, sex, age of vitiligo onset and the VASI score in vitiligo patients.

Material and methods

Patients

The material consisted of skin biopsies collected from 42 Caucasian vitiligo patients of the Dermatology Clinic and skin biopsies collected from 38 Caucasian healthy volunteers hospitalized in the Plastic Surgery Clinic of the University Hospital in Bydgoszcz, Poland. The study was conducted with the consent of the Bioethics Committee of the Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun (Protocol No. 197/2014).

The inclusion criteria of the experimental group were signing the informed consent and diagnosis of vitiligo at least 6 months before the study. Patients with acute inflammatory skin diseases, pregnant women, patients less than 18 years old and incapacitated persons were excluded from the study. The inclusion criteria of the control group was signing the informed consent. The exclusion criteria were diagnosis of vitiligo, personal history or family history of autoimmune diseases, acute and chronic skin diseases, pregnancy, age less than 18 and incapacitation.

The vitiligo patients were asked about the age of vitiligo onset, possible relationship between the occurrence of the first lesions and environmental factors, previous treatment of vitiligo, concomitant autoimmune diseases, family history of vitiligo or other autoimmune diseases, illnesses, surgical procedures, and medications. The extent of skin lesions was assessed based on the VASI (Vitiligo Area Scoring Index) score. Laboratory tests of the blood included morphology, glucose test, thyroid function tests (TSH, fT3, fT4), antithyroglobulin antibodies test, antithyroid peroxidase antibodies test and antinuclear antibodies test.

Methods

The skin biopsies of the experimental group were collected from the centre of the vitiligo lesions and symmetrically from the healthy skin. The skin was not exposed to sunlight/phototherapy and not treated with topical glucocorticosteroids/calcineurin inhibitors for at least 2 months prior to the study. The skin samples of the control group were a part of the material intended for disposal after the completed surgical procedure. They were collected from the sites unexposed to UV radiation. The skin biopsies were stored at –80°C until further analysis.

The isolation of the genomic DNA was performed using a commercially available isolation kit, Genomic Mini A&A Biotechnology. The spectrophotometric analysis was performed to assess the concentration and purity of obtained DNA material. The analysis of the DNA was performed using polymerase chain reaction (PCR) enabling amplification of the specific DNA fragment in a large number of copies in a relatively short period of time. The amplified fragment was exposed to a specific restriction enzyme recognizing the characteristic site within the DNA (restriction fragment length polymorphism, RFLP) (Table 1).

Table 1

Starters used for the PCR reaction in the study (IBB PAN)

GenePolymorphismSequence
PTPN22rs2476601Forward: 5’-TCACCAGCTTCCTCAACCACA-3’
Reverse: 5’-GATAATGTTGCTTCAACGGAATTTA-3’
NLRP1rs2670660Forward: 5’-ATACCCAGGTGTTCAGGAGC-3’
Reverse: 5’-GCCTGTGTTGTACCTTCAGC-3’
NLRP1rs6502867Forward: 5’-TGGGGGTTTGGGTTCTTAG-3’
Reverse: 5’-TTTCTCATGATAGTTTGGGTGTG-3’
TYRrs1393350Forward: 5’-ACGTTGGATGGGAAGGTGAATGATAACACG-3’
Reverse: 5’-ACGTTGGATGATGCGTGCATATCCACCAAC-3’
TYRrs1847134Forward: 5’-TGGGGAGCGTTCCAACAG-3’
Reverse: 5’-TGTTGGCCACCCATGTATTC-3’
G6PDReference geneForward: 5’-TGGGACCTAGCCCTCCATA-3’
Reverse: 5’-AGGGGAATGAGGGAGAGTG-3’

For the isolation of the total RNA, the commercial kit of A&A Biotechnology was used. After the isolation, every sample was analysed for the concentration and purity with the spectrometer. The obtained RNA material was transcribed on the complementary DNA (cDNA) using reverse transcriptase (RT) with a commercial kit dATR RT-PCR EURx and random hexamers as starters. The obtained cDNA was subjected to quantitative analysis qRT-PCR with intercalating dyes EvaGreen and relative quantification of the expression level. As the reference gene, G6PD (glucose-6-phosphate dehydrogenase) gene was used. The UPL (Universal Probe Library) program was used for selection of the reference gene and the starters for examined genes and the reference gene.

Statistical analysis

The statistical analysis was performed using Statistica 13 software. The non-parametric tests were used in the study because of the non-parametric distribution of the results assessed with Shapiro-Wilk test. The Wilcoxon test was used for dependent parameters (comparison of the results obtained within the experimental group). The Spearman’s rank correlation test was used for the assessment of correlation of the analysed parameters. Tests used for assessment of differences between the groups was Mann-Whitney test for two groups and Kruskal-Wallis test for three groups. The test used for the analysis of the variables in the nominal scale was Pearson’s χ2 test and Yates test. At the verification of all analysis the significance factor was α = 0.05, what enabled to consider statistically significant variables at p < 0.05.

Results

42 patients with non-segmental vitiligo and 38 healthy controls were enrolled in the study. The demographic and clinical characteristics of the study subjects are shown in Table 2.

Table 2

Demographic and clinical characteristics of the study subjects

ParameterExperimental group (n = 42)Control group (n = 38)
Demographic details:
 Male, n (%)14 (33.33)14 (36.84)
 Female n (%)28 (66.67)24 (63.16)
 Age, mean ± SD [years]40.98 ±15.0958.45 ±20.20
Clinical details:
 VASI score, mean ± SD5.016 ±2.44
 Age of onset of the disease, mean ± SD [years]29.69 ±15.78
 Duration of the disease, mean ± SD [years]11.29 ±10.53
 Family history of vitiligo, n (%)13 (30.95)
 Personal history of autoimmune18 (42.86%)
Diseases, n (%):
 Autoimmune thyroid diseases14 (33.33)
 Psoriasis3 (7.14)
 Triggering factor, n (%):23 (54.76)
 Emotional stress16 (38.09)
 Sunburn/skin injuries7 (16.67)
Antibodies, n (%):
 Elevated antithyroid peroxidase antibodies11 (26.19)
 Elevated antithyroglobulin antibodies4 (9.52)
 Wlevated antinuclear antibodies10 (23.81)

Table 3 shows differences in the incidence of genotypes between the groups.

Table 3

Statistical analysis of genotype distribution of the PTPN22, NLRP1 and TYR polymorphisms in the experimental and control group

GenotypeExperimental groupControl groupTest resultP-value
N%N%
PTPN22 rs2476601:
 CC1433.331642.1113.6560.001
 CT2252.38615.79
 TT614.291642.11
NLRP1 rs2670660:
 AA819.051847.378.4820.014
 AG1945.24821.05
 GG1535.711231.58
NLRP1 rs6502867:
 CC1740.48923.689.5320.009
 CT2047.621334.21
 TT511.901642.11
TYR rs1393350:
 AA1740.48615.7919.946< 0.001
 AG2457.141642.11
 GG12.381642.11
TYR rs1847134:
 AA819.051334.212.3690.306
 AC1945.241436.84
 CC1535.711128.95

[i] Pearson’s c2 test.

In the case of the rs2476601 polymorphism of the PTPN22 gene, the differences between the groups were statistically significant (p = 0.001). The heterozygous CT genotype was more frequent in the experimental group, while homozygous CC and TT genotypes were more frequent in the control group.

In the case of the rs2670660 polymorphism of the NLRP1 gene, the differences were statistically significant between the investigated groups (p = 0.014). Homozygous GG and heterozygous AG genotypes were more frequent in the experimental group while the homozygous AA genotype was more frequent in the control group. In the case of the rs6502867 polymorphism the differences were also statistically significant (p = 0.009). Homozygous CC and heterozygous CT genotypes were more frequent in the experimental group while the homozygous TT genotype was more frequent in the control group.

In the case of the rs1393350 polymorphism of the TYR gene, the differences between the groups were statistically significant (p < 0.001). The analysis showed that especially the homozygous AA genotype and to a lesser degree the AG genotype were more frequent in the experimental group while the homozygous GG genotype was more frequent in the control group. In the case of the rs1847134 polymorphism the differences were not statistically significant (p = 0.306).

We performed the analysis of the correlation of the investigated gene polymorphisms and incidence of concomitant autoimmune disorders but the results were not statistically significant (p > 0.1).

Statistical analysis of the gene expression

Table 4 shows statistical analysis of the expression of the genes between the healthy skin of the control group and the healthy skin of the experimental group.

Table 4

Statistical analysis of differences in expression of the genes between the healthy skin of the control group and the healthy skin of the experimental group

GroupNxSDMin.Q1MeQ3Max.Test resultP-value
mRNA expression of the PTPN22 gene:
 Experimental421.900.391.01.81.92.02.91.8180.069
 Control381.700.561.01.11.82.03.0
mRNA expression of the NLRP1 gene:
 Experimental4216.61.5313.915.316.717.919.2–6.500< 0.001
 Control3818.40.9017.017.918.319.021.0
mRNA expression of the TYR gene:
 Experimental4214.21.9910.112.514.515.918.2–7.655< 0.001
 Control3820.01.0517.019.520.021.022.0

[i] Mann-Whitney test.

There were no statistically significant differences between the expression of the PTPN22 gene between the healthy skin of the control group and the healthy skin of the experimental group, although there was a statistical trend (p = 0.069). The analysis of the expression of the NLRP1 gene and TYR gene showed statistically significant differences (p < 0.001). In the healthy skin of the experimental group, the expressions of these genes were significantly lower than in the healthy skin of the control group.

Table 5 shows statistical analysis of the expressions of the genes between the lesional and symmetrical non-lesional skin of the experimental group.

Table 5

Statistical analysis of differences in expression of the genes between the lesional and symmetrical non-lesional skin of the experimental group

Skin sampleNxSDMin.Q1MeQ3Max.Test resultP-value
mRNA PTPN22 expression:
 Lesional skin422.940.641.82.42.93.54.05.645< 0.001
 Non-lesional skin421.900.391.01.81.92.02.9
mRNA NLRP1 expression:
 Lesional skin4219.681.2116.319.019.620.921.95.645< 0.001
 Non-lesional skin4216.601.5313.915.316.717.919.2
mRNA TYR expression:
 Lesional skin420.870.150.60.80.91.01.15.645< 0.001
 Non-lesional skin4214.221.9910.112.514.515.918.2

[i] Wilcoxon test.

Analysis of the expression of the investigated genes in lesional and non-lesional skin of the experimental group showed statistically significant differences (p > 0.001). Expressions of the PTPN22 and NLRP1 genes were increased in the lesional skin, and in the case of the TYR gene, the expression was lower comparing to symmetrical non-lesional skin.

We investigated the relationship between the expression of PTPN22, NLRP1 and TYR genes and age of the patients (non-lesional skin) and healthy volunteers. We found a correlation only in the case of the TYR gene and based on Spearman’s rank correlation test, the result was r = –0.375, with p-value of 0.020. The test showed that expression of the TYR gene decreased with age. Conducting an analogous analysis in both groups without any significant difference in age, the correlation was not found (smaller age range excluded the significant relationship).

There was no association between the gene expression and sex in both groups (p > 0.3). We also did not find any statistically significant differences between gene expression and VASI index (p > 0.2) or age of disease onset (p > 0.3) within the experimental group.

The analysis of the association between the genotypes of each investigated polymorphism and gene expression did not show statistically significant results (p > 0.06).

Discussion

The pathogenesis of vitiligo is not fully understood. Genetic studies of polymorphisms and gene expressions are necessary to broaden the knowledge about the disease, determine the genetic risk of the disease and improve the effectiveness of therapies as none of them guarantee full repigmentation of vitiligo lesions.

The experimental group consisted of 42 vitiligo patients. Women constituted 66.67%, and men 33.33%. Many studies showed the same prevalence of the disease in women and men [2629]. But in some studies, as in ours, the disease was more frequent in women, what might be the result of women’s greater attention to aesthetic aspects of the disease [3032].

The average age of first lesions onset in vitiligo patients ranges between 18 and 32 years [28, 29, 33], what is consistent with the experimental group as the average age in the study was 29.69 years.

In the experimental group 54.76% of patients observed a relationship between the lesion occurrence and the environmental factors. Most of them (38.1%) observed the association with emotional stress, others with physical factors (excessive UV exposure/injury). In studies on vitiligo, factors such as malnutrition, stress, injuries, medications, infections and chemical agents were considered to be the main environmental triggering factors, but it is difficult to determine which of them is the most relevant, because the results are divergent [34, 35].

In the study, 30.95% of the patients had a family history of vitiligo. Depending on the population, publications show values ranging from 9% to 36% [27, 3641].

The comorbidity of autoimmune diseases in patients with vitiligo varies between populations (13.1–41.5%) [29, 38, 42]. However, in all cases the frequency is higher than in the general population, where the prevalence of autoimmune diseases reaches 3–8% [43]. In the experimental group, 42.86% of patients had at least one autoimmune disease, most frequently autoimmune thyroid diseases (33.3%).

The PTPN22 gene is located on chromosome 1p 13.3-13.1. It encodes cytoplasmic lymphoid-specific phosphatase (Lyp), which plays an important role in the negative control of T cells activation [8, 9]. The phosphatase is expressed on hematopoietic cells and on cells of the immune system, especially on neutrophils and natural killer cells [44].

Agarwal et al. [45] conducted a meta-analysis of seven studies published up to 2016, including 2,094 cases and 3,613 controls, to verify the association of the 1858 C/T polymorphism of the PTPN22 gene and vitiligo. They concluded that this allele predisposes to vitiligo in Europeans, but not in Asians and Americans. In recent studies, Huraib et al. [46] and Rajendiran et al. [47] showed an association of this polymorphism in the Saudi and South Indian Tamil populations, respectively. However, Akbas et al. [48] did not observe such correlations in the Turkish population.

In our study we showed statistically significant differences (p = 0.001) in the frequency of genotypes between the experimental and the control group, what confirms the association of the 1858 C/T polymorphism of the PTPN22 gene with vitiligo. CT heterozygotes were the most frequent genotype in the experimental group, what is consistent with other studies [46, 47, 49, 50].

Comparing the expression of the PTPN22 gene in the healthy skin of the experimental and the control group the difference was not statistically significant, there was only a statistical trend. However, there was a significant difference (p < 0.001) between lesional and non-lesional skin of the experimental group. Within the vitiligo lesions the expression of the gene was increased.

The results differ from the study conducted by Tang et al. [51] where the gene expression between the lesional and non-lesional skin in patients with vitiligo did not show statistically significant differences (p > 0.05). The study was conducted on a smaller number of samples (17 samples from lesional and 17 samples of non-lesional skin). In addition, biopsies were taken from the lesional skin and from the healthy skin surrounding the lesions, not from distinct symmetrical areas of healthy skin, as in our study.

The inflammasome is a protein complex found mainly in the cytosol of active cells of the immune system. Activation of NLRP1 (NOD-Like Receptor Family Pyrin Domain Containing 1), which is a part of inflammasome, causes release of active caspase-1, IL-1 and IL-18, what induces pyroptosis [52]. The NLRP1 gene is located on chromosome 17. The studies show that in cultured cells even a slight increase in its expression can induce apoptosis [53].

The genetic association of the NLRP1 gene variants with vitiligo was found in studies of the US, UK, Romanian, Jordanian and Indian populations. In the case of rs2670660 and rs6502867 polymorphisms it was shown that they contain high-risk alleles of the disease [18, 19, 54, 55].

In the case of the rs2670660 polymorphism, we concluded that the heterozygous AG genotype predisposes to vitiligo, and the homozygous AA genotype reduces the risk of the disease.

In the case of the rs6502867 polymorphism, we showed that the homozygous CC genotype predisposes to the disease, and the homozygous TT reduces the risk of developing vitiligo.

Results of the Dwivedi et al. [55] analysis differ. In the case of the rs2670660 polymorphism, the AG genotype occurred with a comparable frequency in both groups. In the case of the rs6502867 polymorphism, as in our study, the CC genotype was more frequent in the experimental group, but the difference was not statistically significant.

In the study conducted by Alkhateeb and Qarqaz [54] within the Arab population, in the case of the rs2670660 polymorphism, as in ours, the AG genotype was more frequent in the experimental group and the AA genotype was more frequent in the control group. These results are consistent with our observations, but they were not statistically significant. In the case of the rs6502867 polymorphism in the study of Alkhateeb and Qarqaz [54], the CT genotype was more frequent in the experimental group, what is inconsistent with the results of our research.

Li et al. [56] performed the meta-analysis to investigate the association between rs12150220, rs2670660 and rs6502867 polymorphisms of the NLRP1 gene and vitiligo and concomitant autoimmune diseases. In the case of the rs2670660 polymorphism, they analysed 5 studies with negative results. In the case of the rs6502867 polymorphism they showed a possible increased risk in CC vs. TT+TC genotypes, what is consistent with our results as the CC genotype was the most frequent in the experimental group. As in our study, they did not observe any association between rs2670660 and rs6502867 polymorphisms and concomitant autoimmune diseases in vitiligo patients. The limitations of this meta-analysis were sizes of groups, their heterogeneity and small number of studies that met the requirements of the analysis.

The expression of the NLRP1 gene was significantly higher in the lesional skin comparing to non-lesional skin of the experimental group and healthy skin of the control group (p < 0.001).

Dwivedi et al. [55] and Bhardwaj et al. [57] showed a significantly higher expression of the NLRP1 gene in the blood of vitiligo patients than in the control group. In the latter study, the NLRP1 protein expression was increased in skin samples of patients with active disease. In the study 5 skin biopsies from the patients and 3 biopsies from the healthy volunteers were collected.

Marie et al. [58] showed in 14 vitiligo patients that the expression of the NLRP1 protein was increased in both melanocytes and keratinocytes in the periphery of enlarging vitiligo lesions while the concentration of NLRP1 in the affected skin was mostly low.

Three enzymes, tyrosinase (TYR), tyrosinase related protein 1 (TRP1) and tyrosinase related protein 2 (TRP2), are involved in the melanogenesis process, but only TYR is essential [59]. Many studies showed that tyrosinase is the primary antigen that induces synthesis of autoantibodies in vitiligo patients [6063]. However genetic studies on the TYR gene are not that obvious. Jin et al. [5] conducted the GWAS study in a Caucasian population comparing the genotypes of 1,514 patients with vitiligo with a control group of 2,813 people. Two SNPs (rs1847134 and rs1393350) related to the TYR gene region were identified and haplotype analysis showed a strong association with a block of six SNPs [5].

In our study we showed statistically significant differences in the frequency of genotypes between the experimental and the control group in the case of rs1393350 polymorphism. We showed that the homozygous AA genotype predisposes to vitiligo, while the homozygous GG genotype reduces the risk of developing the disease. These results differ from the results of the study conducted by Jin et al. [5], where the G allele was shown as the risk allele of vitiligo.

In the case of the rs1847134 polymorphism, in our study, there were no statistically significant differences between the groups. However, Jin et al. [5] showed that allele A is the risk allele of vitiligo.

Expression of the TYR gene in the lesional skin was lower comparing to symmetrical non-lesional skin and the skin of the control group. Interestingly, also the expression of the TYR gene in the non-lesional skin of vitiligo patients was significantly lower compared to the control group.

Mansuri et al. [64] analysed the expression of the TYR gene in three groups (lesional and non-lesional skin of the experimental group and healthy skin of the control group) showing results consistent with ours.

Similarly, Yu et al. [65] compared the gene expression in three groups showing a lower expression in vitiligo lesions compared to the non-lesional skin of 23 vitiligo patients and the normal skin of 16 healthy volunteers. Contrary to our study, they did not observe statistically significant differences in the expression of the TYR gene between non-lesional skin of vitiligo patients and the normal skin of the control group.

Some scientists speculate that the decreased expression of most melanocyte-related genes (including TYR) within vitiligo lesions results from the death of melanocytes [65]. However, this does not explain the fact that some studies, including ours, showed that the expression of the TYR gene in patients with vitiligo is also decreased within the skin distant from the vitiligo lesions. It might be a sign of a subclinical melanocyte destruction and genetic predisposition in vitiligo patients.

Our analysis showed genotypes predisposing to vitiligo but did not show genotypes increasing the risk of other autoimmune diseases. The limitation of this study was the size of the experimental group. However, the epidemiological analysis clearly showed an increased incidence of these diseases among vitiligo patients compared to the general population.

We did not show any relationship between polymorphisms of investigated genes and genetic expression, what indicates contribution of additional factors influencing the gene expression, e.g. miRNA molecules or oxidative stress.

We showed statistically significant differences of gene expression both in the lesional and non-lesional skin of the experimental group compared to the control group. Based on these observations, it seems that treatment of the entire surface of the skin may increase the chance of obtaining optimal therapeutic effects and may reduce the risk of developing new lesions.

Conflict of interest

The authors declare no conflict of interest.

References

1 

Mahmoud BH, Hexsel CL, Hamzavi IH. An update on new and emerging options for the treatment of vitiligo. Skin Therapy Letter 2008; 13: 1-6.

2 

Elbuluk N, Ezzedine K. Quality of life, burden of disease, co-morbidities, and systemic effects in vitiligo patients. Dermatol Clin 2017; 35: 117-28.

3 

Jin Y, Andersen G, Yorgov D, et al. Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nat Genet 2016; 48: 1418-24.

4 

Jin Y, Birlea SA, Fain PR, et al. Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat Genet 2012; 44: 676-80.

5 

Jin Y, Birlea SA, Fain PR, et al. Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. N Engl J Med 2010; 362: 1686-97.

6 

Roberts GHL, Santorico SA, Spritz RA. Deep genotype imputation captures virtually all heritability of autoimmune vitiligo. Human Mol Genet 2020; 29: 859-63.

7 

Roberts GH, Spritz RA. Genetics of Vitiligo. eLS. John Wiley & Sons, Ltd, Chichester, UK 2018: 1-10.

8 

Hill R. The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation. Exp Hematol 2002; 30: 237-44.

9 

Smyth D, Cooper JD, Collins JE, et al. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 2004; 53: 3020-3.

10 

Velaga MR, Wilson V, Jennings CE, et al. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocrinol Metabol 2004; 89: 5862-5.

11 

Kyogoku C, Langefeld CD, Ortmann WA, et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Human Genet 2004; 75: 504-7.

12 

Criswell LA, Pfeiffer KA, Lum RF, et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Human Genet 2005; 76: 561-71.

13 

Bottini N, Musumeci L, Alonso A, et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004; 36: 337-8.

14 

Deo S, Bhagat A, Shah R. Genetic variations in NALP1 MRNA expressions in human vitiligo. Indian J Dermatol 2011; 56: 266-71.

15 

Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol 2001; 2: 816-22.

16 

Tschopp J, Martinon F, Burns K. NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol 2003; 4: 95-104.

17 

Dieudé P, Guedj M, Wipff J, et al. NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis. Ann Rheum Dis 2011; 70: 668-74.

18 

Jin Y, Birlea SA, Fain PR, Spritz RA. Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population. J Investig Dermatol 2007; 127: 2558-62.

19 

Jin Y, Mailloux CM, Gowan K, et al. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 2007; 356: 1216-25.

20 

Magitta NF, Bøe Wolff AS, Johansson S et al. A coding polymorphism in NALP1 confers risk for autoimmune Addison’s disease and type 1 diabetes. Genes Immunity 2009; 10: 120-4.

21 

Pontillo A, Vendramin A, Catamo E, et al. The missense variation Q705K in CIAS1/NALP3/NLRP3 gene and an NLRP1 haplotype are associated with celiac disease. Am J Gastroenterol 2011; 106: 539-44.

22 

Sui J, Li H, Fang Y, et al. NLRP1 gene polymorphism influences gene transcription and is a risk factor for rheumatoid arthritis in Han Chinese. Arthritis Rheum 2012; 64: 647-54.

23 

Zurawek M, Fichna M, Januszkiewicz-Lewandowska D, et al. A coding variant in NLRP1 is associated with autoimmune Addison’s disease. Human Immunol 2010; 71: 530-4.

24 

Rezaei N, Gavalas NG, Weetman AP, Kemp EH. Autoimmunity as an aetiological factor in vitiligo. J Eur Acad Dermatol Venereol 2007; 21: 865-76.

25 

Spritz RA, Chiang PW, Oiso N, Alkhateeb A. Human and mouse disorders of pigmentation. Curr Opin Genet Develop 2003; 13: 284-9.

26 

Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: a comprehensive overview Part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. J Am Acad Dermatol 2011; 65: 473-91.

27 

Dogra S, Parsad D, Handa S, Kanwar AJ. Late onset vitiligo: a study of 182 patients. Int J Dermatol 2005; 44: 193-6.

28 

Liu JB, Li M, Yang S, et al. Clinical profiles of vitiligo in China: an analysis of 3742 patients. Clin Exp Dermatol 2005; 30: 327-31.

29 

Mahajan VK, Vashist S, Chauhan PS, et al. Clinico-epidemiological profile of patients with vitiligo: a retrospective study from a Tertiary Care Center of North India. Indian Dermatol OnlineJ 2019; 10: 38-44.

30 

Nunes DH, Esser LMH. Perfil epidemiológico dos pacientes com vitiligo e sua associação com doenças da tireoide. An Brasil Dermatol 2011; 86: 241-8.

31 

Firooz A, Bouzari N, Fallah N, et al. What patients with vitiligo believe about their condition. Int J Dermatol 2004; 43: 811-4.

32 

Borimnejad L, Parsa Yekta Z, Nikbakht-Nasrabadi A, Firooz A. Quality of life with vitiligo: comparison of male and female muslim patients in Iran. Gender Med 2006; 3: 124-30.

33 

Fatani MI, AlSharif SH, Alfif KA, et al. The clinical patterns of vitiligo “hospital-based study” in Makkah region, Saudi Arabia. J Dermatol Dermatol Surg 2014; 18: 17-21.

34 

Jeon IK, Park CJ, Lee MH, et al. A Multicenter Collaborative Study by the Korean Society of Vitiligo about patients’ occupations and the provoking factors of vitiligo. Ann Dermatol 2014; 26: 349-56.

35 

Sehgal VN, Srivastava G. Vitiligo: compendium of clinicoepidemiological features. Indian J Dermatol Venereol Leprology 2007; 73: 149-56.

36 

Shajil E, Agrawal D, Vagadia K, et al. Vitiligo: clinical profiles in Vadodara, Gujarat. Indian J Dermatol 2006; 51: 100-4.

37 

Gopal K, Rama Rao G, Kumar YK, et al. Vitiligo: a part of a systemic autoimmune process. Indian J Dermatol Venereol Leprol 2007; 73: 162-5.

38 

Ingordo V, Cazzaniga S, Raone B, et al. Circulating autoantibodies and autoimmune comorbidities in vitiligo patients: a Multicenter Italian Study. Dermatology 2014; 228: 240-9.

39 

Tanioka M, Yamamoto Y, Katoh M, et al. Vitiligo vulgaris and autoimmune diseases in Japan. Dermatoendocrinology 2009; 1: 43-5.

40 

Vora R, Patel B, Chaudhary A, et al. A clinical study of vitiligo in a rural set up of Gujarat. Indian J Commun Med 2014; 39: 143-6.

41 

Wang X, Du J, Wang T, et al. Prevalence and clinical profile of vitiligo in China: a community-based study in six cities. Acta Dermatovenereol 2013; 93: 62-5.

42 

Dahir AM, Thomsen SF. Comorbidities in vitiligo: comprehensive review. Int J Dermatol 2018; 57: 1157-64.

43 

Chapel H, Haeney M, Misbah S, Snowden N. Immunologia kliniczna. Czelej, Lublin 2009; 103-17.

44 

Begovich AB, Carlton VEH, Honigberg LA, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Human Genet 2004; 75: 330-7.

45 

Agarwal S, Changotra H. Association of protein tyrosine phosphatase, non-receptor type 22 +1858C T polymorphism and susceptibility to vitiligo: systematic review and meta-analysis. Indian J Dermatol Venereol Leprol 2017; 83: 183-9.

46 

Huraib GB, Al Harthi F, Arfin M, et al. Association of functional polymorphism in protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene with vitiligo. Biomarker Insights 2020; 15: 117727192090303.

47 

Rajendiran KS, Rajappa M, Chandrashekar L, Thappa DM. Association of PTPN22 gene polymorphism with non-segmental vitiligo in South Indian Tamils. Adv Dermatol Allergol 2018; 35: 280-5.

48 

Akbas H, Dertlioglu SB, Dilmec F, Atay AE. Lack of association between PTPN22 gene +1858 C&gt;T polymorphism and susceptibility to generalized vitiligo in a Turkish population. Ann Dermatol 2014; 26: 88-91.

49 

Garcia-Melendez Me, Salinas-Santander M, Sanchez-Dominguez C, et al. Protein tyrosine phosphatase PTPN22 +1858C/T polymorphism is associated with active vitiligo. Exp Ther Med 2014; 8: 1433-7.

50 

LaBerge GS, Bennett DC, Fain PR, Spritz RA. PTPN22 is genetically associated with risk of generalized vitiligo, but CTLA4 is not. J Investig Dermatol 2008; 128: 1757-62.

51 

Tang XF, Zhang Z, Hu DY, et al. Association analyses identify three susceptibility Loci for vitiligo in the Chinese Han population. J Investig Dermatol 2013; 133: 403-10.

52 

Tang L, Zhou F. Inflammasomes in common immune-related skin diseases. Front Immunol 2020; 11: 882.

53 

Wang NS, Unkila MT, Reineks EZ, Distelhorst CW. Transient expression of wild-type or mitochondrially targeted Bcl-2 induces apoptosis, whereas transient expression of endoplasmic reticulum-targeted Bcl-2 is protective against Bax-induced cell death. J Biol Chem 2001; 276: 44117-28.

54 

Alkhateeb A, Qarqaz F. Genetic association of NALP1 with generalized vitiligo in Jordanian Arabs. Arch Dermatol Res 2010; 302: 631-4.

55 

Dwivedi M, Laddha NC, Mansuri MS, et al. Association of NLRP1 genetic variants and mRNA overexpression with generalized vitiligo and disease activity in a Gujarat population. Br J Dermatol 2013; 169: 1114-25.

56 

Li J, Yan M, Zhang Y, et al. Meta-analysis of the association between NLRP1 polymorphisms and the susceptibility to vitiligo and associated autoimmune diseases. Oncotarget 2017; 8: 88179-88.

57 

Bhardwaj S, Rani S, Kumaran MS, et al. Expression of Th17‐ and Treg-specific transcription factors in vitiligo patients. Int J Dermatol 2020; 59: 474-81.

58 

Marie J, Kovacs D, Pain C, et al. Inflammasome activation and vitiligo/nonsegmental vitiligo progression. Br J Dermatol 2014; 170: 816-23.

59 

Niu C, Aisa HA. Upregulation of melanogenesis and tyrosinase activity: potential agents for vitiligo. Molecules 2017; 22: 1303.

60 

Al-Shobaili HA, Rasheed Z. Oxidized tyrosinase: a possible antigenic stimulus for non-segmental vitiligo autoantibodies. J Dermatol Sci 2015; 79: 203-13.

61 

Baharav E, Merimski O, Shoenfeld Y, et al. Tyrosinase as an autoantigen in patients with vitiligo. Clin Exp Immunol 1996; 105: 84-8.

62 

Merimsky O, Shoenfeld Y, Baharav E, et al. Reactivity to tyrosinase: expression in cancer (melanoma) and autoimmunity (vitiligo). Human Antibodies Hybridomas 1996; 7: 151-6.

63 

Zhu MC, Liu CG, Wang DX, Zhan Z. Detection of serum anti-melanocyte antibodies and identification of related antigens in patients with vitiligo. Genet Mol Res 2015; 14: 16060-73.

64 

Mansuri MS, Singh M, Begum R. miRNA signatures and transcriptional regulation of their target genes in vitiligo. J Dermatol Sci 2016; 84: 50-8.

65 

Yu R, Broady R, Huang Y, et al. Transcriptome analysis reveals markers of aberrantly activated innate immunity in vitiligo lesional and non-lesional skin. PLoS One 2012; 7: e51040.

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