University of Oulu

Laine, A.-P., Valta, M., Toppari, J., Knip, M., Veijola, R., Ilonen, J., & Lempainen, J. (2022). Non-hla gene polymorphisms in the pathogenesis of type 1 diabetes: Phase and endotype specific effects. Frontiers in Immunology, 13, 909020.

Non-HLA gene polymorphisms in the pathogenesis of type 1 diabetes : phase and endotype specific effects

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Author: Laine, Antti-Pekka1; Valta, Milla1; Toppari, Jorma2,3;
Organizations: 1Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
2Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, University of Turku, Turku, Finland
3Department of Paediatrics, University of Turku and Turku University Hospital, Turku, Finland
4Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
5Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
6Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland
7Department of Paediatrics, PEDEGO Research Unit, Medical Research Center, University of Oulu, Oulu, Finland
8Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
9Clinical Microbiology, Turku University Hospital, Turku, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.3 MB)
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Language: English
Published: Frontiers Media, 2022
Publish Date: 2023-03-10


The non-HLA loci conferring susceptibility to type 1 diabetes determine approximately half of the genetic disease risk, and several of them have been shown to affect immune-cell or pancreatic β-cell functions. A number of these loci have shown associations with the appearance of autoantibodies or with progression from seroconversion to clinical type 1 diabetes. In the current study, we have re-analyzed 21 of our loci with prior association evidence using an expanded DIPP follow-up cohort of 976 autoantibody positive cases and 1,910 matched controls. Survival analysis using Cox regression was applied for time periods from birth to seroconversion and from seroconversion to type 1 diabetes. The appearance of autoantibodies was also analyzed in endotypes, which are defined by the first appearing autoantibody, either IAA or GADA. Analyzing the time period from birth to seroconversion, we were able to replicate our previous association findings at PTPN22, INS, and NRP1. Novel findings included associations with ERBB3, UBASH3A, PTPN2, and FUT2. In the time period from seroconversion to clinical type 1 diabetes, prior associations with PTPN2, CD226, and PTPN22 were replicated, and a novel association with STAT4 was observed. Analyzing the appearance of autoantibodies in endotypes, the PTPN22 association was specific for IAA-first. In the progression phase, STAT4 was specific for IAA-first and ERBB3 to GADA-first. In conclusion, our results further the knowledge of the function of non-HLA risk polymorphisms in detailing endotype specificity and timing of disease development.

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Series: Frontiers in immunology
ISSN: 1664-3224
ISSN-E: 1664-3224
ISSN-L: 1664-3224
Volume: 13
Article number: 909020
DOI: 10.3389/fimmu.2022.909020
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
3111 Biomedicine
Funding: This work was funded by the Sigrid Jusélius Foundation, the Finnish Medical Foundation, the Juvenile Diabetes Research Foundation (JDRF), grant number 3-SRA-2020-955-S-B and the Academy of Finland grant number 286765.
Copyright information: © 2022 Laine, Valta, Toppari, Knip, Veijola, Ilonen and Lempainen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.