Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells

• Published in: European journal of immunology Vol. 50; no. 4; pp. 581 - 588
• Main Authors: Valta, Milla, Gazali, Ahmad Mahfuz, Viisanen, Tyyne, Ihantola, Emmi‐Leena, Ekman, Ilse, Toppari, Jorma, Knip, Mikael, Veijola, Riitta, Ilonen, Jorma, Lempainen, Johanna, Kinnunen, Tuure
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.04.2020
• Subjects: Alleles; Autoantibodies; Autoimmune diseases; Autoimmunity; CD25 antigen; CD4 antigen; CTLA-4 protein; Diabetes; Diabetes mellitus (insulin dependent); ErbB-3 protein; Flow cytometry; Foxp3 protein; Gene polymorphism; Haplotypes; Histocompatibility antigen HLA; Human; Immunoregulation; Interleukin 2 receptors; Lymphocytes T; Peripheral blood; Protein-tyrosine-phosphatase; PTPN2 protein; PTPN22; Regulatory T cells; Single-nucleotide polymorphism; Type 1 diabetes; Autoimmunity; Human; PTPN22; Regulatory T cells; Type 1 diabetes
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.201948378

Dysfunction of FOXP3‐positive regulatory T cells (Tregs) likely plays a major role in the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). Whether genetic polymorphisms associated with the risk of autoimmune diseases affect Treg frequency or function is currently unclear. Here, we analysed the effect of T1D‐associated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non‐HLA genes [INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243), and ERBB3 (rs2292239)] on peripheral blood Treg frequencies. These were determined by flow cytometry in 65 subjects who had progressed to T1D, 86 islet autoantibody‐positive at‐risk subjects, and 215 islet autoantibody‐negative healthy controls. The PTPN22 rs2476601 risk allele A was associated with an increase in total (p = 6 × 10−6) and naïve (p = 4 × 10−5) CD4+CD25+CD127lowFOXP3+ Treg frequencies. These findings were validated in a separate cohort comprising ten trios of healthy islet autoantibody‐negative children carrying each of the three PTPN22 rs2476601 genotypes AA, AG, and GG (p = 0.005 for total and p = 0.03 for naïve Tregs, respectively). In conclusion, our analysis implicates the autoimmune PTPN22 rs2476601 risk allele A in controlling the frequency of Tregs in human peripheral blood. Individuals carrying the PTPN22/rs2476601 autoimmunity risk allele A display elevated circulating Treg frequencies. This increase appears to be explained by a change in naïve but not memory Tregs. Patients with type 1 diabetes have higher circulating Treg frequencies also in the absence of the PTPN22/rs2476601 autoimmunity risk allele A