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A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo


Vitiligo is an acquired hypomelanotic skin disorder resulting from the loss of functional melanocytes from the cutaneous epidermis and autoimmunity has been suggested to play a part in its pathogenesis. Recently, the missense R620W polymorphism in the PTPN22 gene, which encodes lymphoid protein tyrosine phosphatase (LYP), has been associated with susceptibility to autoimmune disorders. The objective of this study was to ascertain if the disease-associated 1858T allele was also associated with generalised (nonsegmental) vitiligo and so the frequencies of the PTPN22 1858C/T alleles were investigated in 165 English patients with generalised vitiligo and 304 ethnically matched control subjects. The results indicated that the 1858T allele was significantly over-represented in the vitiligo patient group compared with the control cohort. Of 330 vitiligo alleles, 48 (14.5%) encoded the Trp620 variant compared to 52 of 608 (8.6%) control alleles (P=0.006; odds ratio=1.82, 95% confidence interval=1.17–2.82). The results indicate that the LYP missense R620W polymorphism may have an influence on the development of generalised vitiligo and provide further evidence for autoimmunity as an aetiological factor with respect to this disease.


Vitiligo is an acquired hypomelanotic skin disorder characterised by circumscribed depigmented macules resulting from the loss of functional melanocytes from the cutaneous epidermis. Although the aetiology of vitiligo remains obscure, autoimmunity has been suggested to play a role in the pathogenesis of the disease.1 Support for this theory arises from the frequent association of vitiligo with autoimmune disorders and the demonstration of autoantibodies to melanosomal proteins in the serum of patients with the disease.2, 3, 4, 5, 6 More recently, autoreactive cytotoxic T lymphocytes (CTLs), which specifically recognise melanocyte differentiation antigens, have been detected in both the peripheral blood and perilesional skin of individuals with vitiligo.7, 8, 9 Furthermore, several genes that have a role in regulating immunity have been associated with susceptibility to vitiligo including: polymorphic markers in the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene, the autoimmune susceptibility loci AIS1, AIS2, AIS3 and SLEV1 and certain human leukocyte antigen specificities of the major histocompatibility complex.10, 11, 12, 13, 14, 15, 16, 17

Recently, the missense R620W polymorphism in the PTPN22 gene at nucleotide 1858 (1858C → T) in codon 620 (620Arg → Trp) has been associated with autoimmune diseases including type I diabetes mellitus, Graves' disease, systemic lupus erythematosus and rheumatoid arthritis.18, 19, 20, 21, 22, 23, 24, 25 The gene, located on chromosome 1p13,19 encodes lymphoid protein tyrosine phosphatase (LYP), which is important in the negative control of T lymphocyte activation.26 Lymphoid protein tyrosine phosphatase is expressed in T lymphocytes and associates with C-terminal Src kinase (CSK) to form a complex that suppresses the T-cell receptor signalling kinases LCK and FYN.27, 28 Experimental evidence suggests that the disease-associated LYP variant Trp620 prevents the interaction of LYP with CSK.18 Consequently, the T-cell receptor-associated kinases might be able to induce T-cell activation in an uncontrolled manner and this may increase the overall reactivity of the immune system and predispose an individual to autoimmune disease. Since generalised (nonsegmental) vitiligo may have an autoimmune aetiology, the frequencies of the PTPN22 1858C/T genotypes in 165 English patients with generalised vitiligo and 304 ethnically matched controls were examined in a case–control study using a restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) genotyping method.


The frequency of 1858C/T alleles in the vitiligo patient and control groups

Full genotype and allele data are shown in Table 1. The results indicate that the T nucleotide at codon 620, which encodes the Trp-carrying allele, is significantly over-represented in 165 patients with generalised vitiligo compared with 304 control subjects. Of the 330 vitiligo patient alleles analysed, 48 (14.5%) were found to encode the disease-associated LYP variant Trp620, compared to 52 of 608 (8.6%) control alleles (P=0.006; odds ratios (OR)=1.82, 95% confidence intervals (95% CI)=1.17–2.82). In the subgrouping of patients with generalised vitiligo and no other autoimmune disorder, the 1858T allele also occurred at a significantly greater frequency than in the control group: of 226 alleles, 35 (15.5%) encoded Trp620 (P=0.005; OR=1.96, 95% CI=1.21–3.18).

Table 1 Distribution of alleles and genotypes for the PTPN22 1858C/T polymorphism in patients with generalised vitiligo and in control subjects


The PTPN22 gene product LYP is an important downregulator of T lymphocyte activation. Knockout mice deficient for PTPN22 show selective dysregulation in the effector/memory T-cell compartment, with hyperproliferation and early signalling responses in restimulated T cells, compared with essentially normal responses in naïve T lymphocytes.29 High-level spontaneous germinal centre formation and elevated titres of T-cell-dependent antibodies immunoglobulin (Ig) G1 and IgG2 are also demonstrated in PTPN22 knockouts.29 Furthermore, RNAi experiments have demonstrated that reduced LYP expression in Jurkat's cells occurs concomitantly with an increase in the expression of T-cell receptor-dependent activation.25 The downregulatory activity of LYP is mediated as a complex with CSK, which suppresses the T-cell receptor signalling kinases LCK and FYN. Recently, the 1858T allele encoding Trp at amino-acid residue 620 of the PTPN22 gene has been shown to dramatically reduce the binding of LYP to CSK in vitro.18 This has been suggested to disrupt the downregulation of T-cell activation so that T cells lacking a LYP-CSK complex are likely to be hyper-reactive and more readily able to mount an autoimmune response.

Several studies have associated the 1858T allele with autoimmune diseases18, 19, 20, 21, 22, 23, 24, 25 and generalised vitiligo is thought to have an autoimmune aetiology,1 although this remains undefined. The frequent association of vitiligo with autoimmune disorders and the demonstration of autoantibodies to melanosomal proteins in the serum of patients with the disease support this theory.2, 3, 4, 5, 6 In addition, autoreactive CTLs, which specifically recognise melanocyte differentiation antigens, have been detected in both the peripheral blood and perilesional skin of individuals with vitiligo.7, 8, 9 Melanocyte-specific CTLs have also been identified in patients with melanoma where vitiligo has occurred during immunotherapy and the adoptive transfer of melanoma antigen-specific CTLs may be associated with the regression of melanoma metastases and the appearance of vitiligo.30, 31, 32 Experiments in murine models have also demonstrated that CTLs to melanocytic antigens can cause the destruction of pigment cells leading to vitiligo-like fur depigmentation.33 These observations provide evidence of T-cell-mediated vitiligo in both humans and mice and suggest that unregulated T-cell activity may contribute to the development of the disease. The results reported here in that the PTPN22 disease-associated 1858T allele is also associated with generalised vitiligo add evidence to the theory that T cells are involved in the pathogenesis of the disorder. The Trp620 variant of PTPN22 may predispose individuals to the development of vitiligo either as a result of the reactivity of CTLs that are cytotoxic to melanocytes7, 8, 9 or as a result of the generation of autoantibodies that can destroy pigment cells.34, 35

Previously, several genes that have a role in regulating immunity have been associated with susceptibility to vitiligo. The study of major histocompatibility complex genes has revealed associations of vitiligo with certain human leukocyte antigens.16, 17 Polymorphic markers in the CTLA-4 gene that are associated with autoimmunity are also associated with vitiligo that occurs with other autoimmune disorders.10, 11, 12 Vitiligo can also develop as part of autoimmune polyendocrine syndrome type 1, a disease resulting from mutations in the autoimmune regulator (AIRE) gene.36 Likewise, the autoimmune susceptibility loci AIS1, AIS2 and SLEV1 are associated with generalised vitiligo that occurs with other autoimmune conditions.13, 14, 15 In contrast, generalised vitiligo that presents in individuals without other autoimmune disorders is associated with AIS3.13, 14, 15 In the present study, the disease-associated PTPN22 1858T allele appears to be associated with generalised vitiligo that develops without the concomitant occurrence of other autoimmune diseases, suggesting that the basis of generalised vitiligo might still be autoimmune in nature.

The finding that the 1858T allele of the PTPN22 R620W polymorphism is associated with generalised vitiligo and other autoimmune conditions supports the hypothesis that there are common genetic variants that contribute to general immune-dysregulation and susceptibility to autoimmunity.37 Although it is tempting to speculate a common underlying mechanism for autoimmunity, given the expression of this molecule in many immunologically relevant cell types, it remains possible that PTPN22 may act in different ways in different autoimmune diseases.

Materials and methods

Patients and controls

The 165 English vitiligo patients (66 male, 99 female; mean age: 52 years; age range 21–85 years; mean age at disease onset: 34 years; age range at disease onset: 7–73 years) included in this study were examined in dermatology and endocrinology clinics in Sheffield, UK. Patients were characterised with generalised vitiligo including symmetrical, 120; symmetrical/peri-orificial, 13; peri-orificial, three; acrofacial, 19; symmetrical/acrofacial, nine; symmetrical/peri-orificial/acrofacial, one. The presence of associated autoimmune disorders was also determined. No other autoimmune disease was reported in 113 patients, and 52 subjects had at least one other autoimmune disorder: autoimmune thyroid disease, 31; alopecia areata, five; psoriasis, one; systemic lupus erythematosus, two; rheumatoid arthritis, one; diabetes mellitus, three; scleroderma, one; multiple autoimmune disorders, eight. The 304 healthy controls (152 male, 152 female; mean age: 43 years; age range: 19–65 years) had no clinical evidence or family history of vitiligo or of any other autoimmune disorder and were ethnically matched to the disease population. The Ethics Committee of the Northern General Hospital, Sheffield, UK approved this work and all subjects gave informed consent.

DNA isolation and genotyping

High molecular weight genomic DNA was prepared from heparinised venous blood samples (10–20 ml) using a Gentra Systems Puregene DNA Isolation Kit (Flowgen, Lichfield, UK) according to the manufacturer's instructions. The PTPN22 1858C/T genotypes were determined by a RFLP-PCR genotyping method. Oligonucleotide primers (Invitrogen, Paisley, UK) for PCR amplification were designed to amplify a 220-base pair fragment of the PTPN22 gene as previously detailed.18 The primers used were IndexTerm5′-TCACCAGCTTCCTCAACCACA-3′ and IndexTerm5′-GATAATGTTGCTTCAACGGAATTTA-3′.

PCR amplification was performed in 50-μl reactions containing 50 ng of genomic DNA, 2.5 U of Taq DNA polymerase (Promega, Southampton, UK), 0.1 mM of dATP, dGTP, dCTP and dTTP (Promega), 1 μM of each primer, 1.5 mM MgCl2, 10 mM Tris-HCl (pH 9.0), 50 mM KCl and nuclease-free water to 50 μl. Amplifications of 35 cycles were carried out in a DNA Thermal Cycler (Perkin-Elmer Cetus, Norwalk, CT, USA) using cycles of 94°C for 1 min, 55°C for 1 min and 72°C for 1 min, followed by a final extension of 10 min at 72°C. Amplicons were digested with the restriction enzyme XcmI (New England BioLabs, Hitchin, UK) at 37°C for 2 h in 30-μl reactions containing 50 mM NaCl, 10 mM Tris-HCl (pH 7.9), 10 mM MgCl2, 1 mM dithiothreitol and 2 U of XcmI. The digestion products were separated in 2.5% (w/v) agarose gels along with 100-base pair size markers (Promega) and were then visualised under UV light following staining with ethidium bromide. The presence of the T nucleotide at position 1858 (codon 620 encoding Trp) was indicated by cleavage of the PCR product. Positive controls for each genotype, which had been determined by DNA sequencing, were included on each gel. The accuracy of the genotyping protocol was verified by repeating the RFLP-PCR analysis on 60 (12%) randomly chosen DNA samples. All initial results were verified in the reanalysed samples.

Statistical analyses

The frequencies of the PTPN22 1858C/T alleles and genotypes were compared between vitiligo patient and control groups using a χ2 test on 2 × 2 and 2 × 3 contingency tables. P-values <0.05 (two-tailed) were regarded as significant. OR with 95% CI were calculated according to a previous method.38


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Correspondence to E H Kemp.

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Cantón, I., Akhtar, S., Gavalas, N. et al. A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo. Genes Immun 6, 584–587 (2005).

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  • autoimmunity
  • gene polymorphism
  • genetic susceptibility
  • melanocyte
  • pigmentation
  • vitiligo

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