Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes: Phase and Endotype Specific Effects.

Autor:	Laine AP; Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland., Valta M; Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland., Toppari J; Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, University of Turku, Turku, Finland.; Department of Paediatrics, University of Turku and Turku University Hospital, Turku, Finland., Knip M; Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland., Veijola R; Department of Paediatrics, PEDEGO Research Unit, Medical Research Center, University of Oulu, Oulu, Finland.; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland., Ilonen J; Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland., Lempainen J; Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.; Department of Paediatrics, University of Turku and Turku University Hospital, Turku, Finland.; Clinical Microbiology, Turku University Hospital, Turku, Finland.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Jun 21; Vol. 13, pp. 909020. Date of Electronic Publication: 2022 Jun 21 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.909020
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Laine, Valta, Toppari, Knip, Veijola, Ilonen and Lempainen.)
Databáze:	MEDLINE
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