The PTPN22 R620W polymorphism is associated with inclusion body myositis: data from the UKMyoNet study

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A genetic association is described between the PTPN22 rs2476601 R620W polymorphism and inclusion body myositis. Dear Editor, Idiopathic inflammatory myopathies (IIMs) are regarded as systemic autoimmune diseases influenced by both genetic susceptibility and environmental exposures. Beyond the strongest genetic factor-the HLA 8.1 ancestral haplotype (8.1AH) [1, 2], the protein tyrosine phosphatase 22 (PTPN22) gene R620W variant (rs2476601) has previously been associated with IIM and the polymyositis (PM) subgroup specifically [3]. An up-to-date stratification of IIM clinical subtypes, incorporating myositis-specific autoantibodies (MSAs), may enable further insights into the association of PTPN22 and IIM. Moreover, accumulating evidence suggests that smoking is associated with a risk of high autoantibody levels and the development of comorbidities in autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus [4, 5]. Possible interactions between HLA-DRB1*03:01 and smoking on the risk of PM and anti-Jo1 have been reported [6]. However, the impact of genetic markers and smoking on other clinical subtypes and MSAs remains insufficiently explored. In this study, we sought to investigate the clinical and autoantibody specificity of the PTPN22 rs2476601 association in patients with IIM and stratified by smoking status, using data from a national multicentre registry (UKMyoNet). A cross-sectional, case-control study was conducted to investigate the association of PTPN22 rs2476601 with IIM subtypes (methods and case ascertainment previously described) [7]. The cohort comprised 626 cases diagnosed with dermatomyositis (DM), anti-synthetase syndrome (ASyS), immune-mediated necrotizing myopathy (IMNM), inclusion body myositis (IBM) or overlap myositis (OM) and 7482 healthy controls. Smoking data were available for 521 patients. MSA frequencies were compared by smoking history and PTPN22 rs2476601 status. Sera were tested for MSAs and myositis-associated autoantibodies (MAAs) using immunoprecipitation, line blot and ELISA, as described previously [1]. The MSA panel included anti-MDA5, anti-NXP2, anti-SAE, anti-Mi-2, anti-TIF-1γ, anti-SRP, anti-HMGCR, anti-synthetase autoantibodies (anti-Jo-1, anti-PL-7 and anti-PL-12) and anti-cN1A. Anti-cN1A was prespecified as an MSA because of its enrichment in IBM and its adoption as an IBM-defining marker in recent studies, although we acknowledge that some classify it as an MAA due to occasional detection in non-myositis autoimmune diseases. The MAA panel included PM/Scl, Ro52 and RNP autoantibodies. Genotyping was performed according to Illumina’s protocols at the Centre for Genetics and Genomics Vs Arthritis, University of Manchester. Associations between rs2476601 and myositis subgroups or MSAs were evaluated using χ2 tests. Patients with IIM were stratified into the following subgroups: 171 with DM (114 MSA-positive), 154 with ASyS (153 MSA-positive), 31 with IMNM (30 MSA-positive), 112 with IBM (51 MSA-positive) and 158 with OM (146 MSA-positive). Subgroup analysis revealed a significant association for rs2476601 between the IBM clinical sub-group vs controls (P = 0.005, Odds Ratio (OR) = 1.957; 95% confidence interval (CI) = 1.307–2.931). There was a trend towards significance in the ASyS clinical sub-group (P = 0.063, OR = 1.511; 95% CI = 1.049–2.176) (Table 1). Association of rs2476601-A with clinical subtypes of myositis Note: ASyS, anti-synthetase syndrome; CI, confidence interval; DM, dermatomyositis; HC, healthy control; IBM, inclusion body myositis; IIM, idiopathic inflammatory myopathy; IMNM, immune-mediated necrotizing myopathy; OM, overlap myositis; OR, odds ratio; n (%), carriers of the rs2476601-A allele, including both heterozygotes and homozygotes. Association of rs2476601-A with clinical subtypes of myositis Note: ASyS, anti-synthetase syndrome; CI, confidence interval; DM, dermatomyositis; HC, healthy control; IBM, inclusion body myositis; IIM, idiopathic inflammatory myopathy; IMNM, immune-mediated necrotizing myopathy; OM, overlap myositis; OR, odds ratio; n (%), carriers of the rs2476601-A allele, including both heterozygotes and homozygotes. A further analysis was conducted with data stratified by antibody subgroup. No significant association was observed by antibody status and, in particular, no specific rs2476601 association was observed with cN1A autoantibodies, known to be associated with IBM. A weak association was observed for patients with anti-Jo-1 and anti-SAE1 antibodies (Supplementary Table S1), which was lost after correction for multiple comparisons. No significant associations were found with other MSAs, including anti-MDA5, NXP2, SRP, HMGCR, PM/Scl, Ro52 or RNP autoantibodies. To explore gene–environment interactions of smoking and rs2476601 on MSA frequencies in myositis, patients were stratified into four groups based on smoking history and rs2476601-A carrier status (Supplementary Table S2). Never-smokers without rs2476601-A were used as the reference group. In descriptive analyses, ever-smokers carrying rs2476601-A had 2.2 times increased odds of anti-cN1A positivity compared with the reference group, although this was not statistically significant. In contrast, ever-smokers without rs2476601-A had 2.6 times increased odds of anti-cN1A positivity (P = 0.026, OR = 2.613; 95% CI = 1.087–6.284). A contrasting pattern was observed for anti-Ro52, with ever-smokers lacking rs2476601-A showing a significantly lower frequency of positivity (P = 0.039, OR = 0.507; 95% CI = 0.264–0.973). Our findings extend previous associations between rs2476601 and IIM. While PTPN22 was reported to be associated with PM [1], following further analysis using the updated classification of myositis—which separates IBM from the original PM classification—rs2476601 was found to be associated primarily with the IBM subtype. Notably, this association was not observed in anti-cN1A-positive IBM patients, suggesting heterogeneity even within the IBM subgroup. Furthermore, we observed differences in anti-cN1A antibody frequency across strata defined by smoking history and rs2476601 genotype, consistent with a potential gene–environment interaction. In conclusion, this study identifies a novel association between PTPN22 rs2476601 and IBM, highlighting the importance of updated classification and stratification in genetic studies. Our findings also raise the possibility of gene–environment interactions influencing autoantibody profiles in IIM, which are worthy of further investigation in larger, prospective studies. Supplementary material is available at Rheumatology online. The data underlying this article will be shared on reasonable request to the corresponding author. This study has been delivered through the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (NIHR203308). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. YH.L. is supported by the China Scholarship Council (CSC) (202406010039). Disclosure statement: The authors have declared no conflicts of interest. Ethical approval: Collection of data and blood from patients was obtained under the regulation of ethics committee approval (MREC 98/8/86).

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