University of Oulu

Valta, M., Gazali, A.M., Viisanen, T., Ihantola, E.‐L., Ekman, I., Toppari, J., Knip, M., Veijola, R., Ilonen, J., Lempainen, J. and Kinnunen, T. (2020), Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells. Eur. J. Immunol., 50: 581-588. doi:10.1002/eji.201948378

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

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Author: Valta, Milla1; Gazali, Ahmad Mahfuz2; Viisanen, Tyyne2;
Organizations: 1Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
2Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
3Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
4Department of Pediatrics, Turku University Hospital, Turku, Finland
5Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
6Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland
7Folkhälsan Research Center, Helsinki, Finland
8Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland
9Department of Pediatrics, PEDEGO Research Unit, Medical Research Center, University of Oulu, Oulu, Finland and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
10Clinical Microbiology, Turku University Hospital, Turku, Finland
11Eastern Finland Laboratory Centre (ISLAB), Kuopio, Finland
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe2020060140050
Language: English
Published: John Wiley & Sons, 2020
Publish Date: 2020-12-06
Description:

Abstract

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.

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Series: European journal of immunology
ISSN: 0014-2980
ISSN-E: 1521-4141
ISSN-L: 0014-2980
Volume: 50
Issue: 4
Pages: 581 - 588
DOI: 10.1002/eji.201948378
OADOI: https://oadoi.org/10.1002/eji.201948378
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
3111 Biomedicine
Subjects:
Funding: Both TK and JI were supported by the Academy of Finland (Decision numbers 307320 to TK and 286765 to JI) and the Sigrid Juselius Foundation. Additionally, TK was supported by the Finnish Diabetes Research Foundation, JL by the Emil Aaltonen Foundation, and RV by JDRF.
Copyright information: © 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. This is the peer reviewed version of the following article: Valta, M., Gazali, A.M., Viisanen, T., Ihantola, E.‐L., Ekman, I., Toppari, J., Knip, M., Veijola, R., Ilonen, J., Lempainen, J. and Kinnunen, T. (2020), Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells. Eur. J. Immunol., 50: 581-588, which has been published in final form at https://doi.org/10.1002/eji.201948378. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.