Meta-Analysis of 1858C→T Polymorphism in the PTPN22 Gene Demonstrates Lack of Association with Risk for Vitiligo

Dear Editor, Vitiligo is a pigmentary disorder associated with the selective loss of melanocytes, leading to skin depigmentation.[1] Numerous genes have been linked to the pathophysiology of vitiligo through linkage and association studies. The PTPN22 gene is considered one of the most critical risk factors for vitiligo.[2] It has been demonstrated that a polymorphism in PTPN22 disrupts the function of the enzyme and may put a person at risk for autoimmune disease by disrupting the interaction between the C-terminal src kinase and lymphoid tyrosine phosphatase.[3] A common allele variant of PTPN22 is rs2476601. The 1858C→T polymorphism has three genotypes (CC, CT, and TT). The mutation (C→T) results in the substitution of amino acids from arginine to tyrosine, thereby decreasing PTPN22 activity.[4] A previous meta-analysis conducted between 2005 and 2014 reported that PTPN22 was significantly associated with vitiligo (odds ratio [OR] = 1.53, 95% confidence interval [CI] [1.34–1.75], P < 0.001). However, the findings remain inconsistent.[5] Therefore, we performed an updated meta-analysis from 2018 to 2023 to pursue a more precise estimation of the association, obtain new inspiration, and provide a scientific basis for the prevention and further mechanistic studies of vitiligo. A thorough exploration of the literature was performed by searching various databases, including Google Scholar, PubMed, and DogPile. This search aimed to find published studies that evaluated the relationship between PTPN22 (rs2476601) and the likelihood of developing vitiligo. Five articles conformed to the standards. In the updated meta-analysis, we used crude ORs with 95% CIs to evaluate the strength of the relationship between PTPN22 1858C→T polymorphism and the risk of vitiligo. The risks of the allelic, recessive, dominant, and over-dominant models were evaluated. To assess heterogeneity among the studies, the Chi-square test was used when P>0.05, heterogeneity was considered absent, and a fixed-effects model (Mantel-Haenszel method) was adopted to calculate the pooled OR. Otherwise, we applied a random-effects model (the Der Simonian and Laird method). These two models provided similar results when between-study heterogeneity was absent. To evaluate potential publication bias, funnel plots and the linear regression asymmetry test developed by Egger’s test were used. Risk bias was evaluated to thoroughly assess the methodological quality of the selected studies. All statistical analyses were performed using MetaGenyo software and Cochrane Rob tool 2. Consequently, 11 eligible articles including 2612 cases and 4212 controls were included in our updated meta-analysis. There were seven studies of Asians and four studies of Europeans, and the distribution of genotypes in the controls of all studies agreed with HWE, except for one in Figure 1.Figure 1: Characteristics of the studies for a PTPN22 rs2476001 gene polymorphism with vitiligo. HWE: Hardy-Weinberg equilibriumAnalysis of the data revealed no significant association between the PTPN22 1858C→T polymorphism and the risk of vitiligo in the overall population. In the allelic model (C vs. T), the OR was 0.55 (95% CI [0.28–1.08], P = 0.14). Similarly, in the dominant model (TT + CT vs. CC), the OR was 0.81 (95% CI [0.15–4.37], P = 0.81), and in the recessive model (TT vs. CT + CC), the OR was 0.44 (95% CI [0.19–1.04], P = 0.1). Additionally, the over-dominant model (CT vs. CC) showed an OR of 2.49 (95% CI [1.04–5.96], P = 0.07) [Figure 2]. In funnel plots, no obvious bias was identified in this study. Risk bias suggests a significantly low degree of bias for the selected studies [Figure 3].Figure 2: (a) The forest plots provide no significant association between the PTPN22 rs2476601 polymorphism with vitiligo risk in the allelic genetic model. (b) The forest plots provide no significant association between the PTPN22 rs2476601 polymorphism with vitiligo risk in the dominant genetic model. (c) The forest plots provide no significant association between the PTPN22 rs2476601 polymorphism with vitiligo risk in the recessive genetic model. (d) The forest plots provide no significant association between the PTPN22 rs2476601 polymorphism with vitiligo risk in the over-dominant genetic modelFigure 3: (a) The distribution of the investigated PTPN22 rs2476601 among vitiligo cases and control. (b) Risk of bias summary and graph for investigating PTPN22 and rs2476601 gene polymorphismThis updated meta-analysis contains 11 eligible studies providing data on the correlation between 1858C→T polymorphism and the susceptibility of vitiligo, from the result of the updated meta-analysis. However, it is difficult to determine how low PTPN22 activity increases the risk of vitiligo. In summary, the results of our updated meta-analysis suggest that the PTPN22 1858C→T polymorphism is not associated with the risk of vitiligo. Future well-designed large-scale studies are warranted to validate the association between PTPN22 1858C→T and the risk of vitiligo. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.