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

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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 , vol. 13 , 909020 . https://doi.org/10.3389/fimmu.2022.909020

Title: Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes : Phase and Endotype Specific Effects
Author: Laine, Antti-Pekka; Valta, Milla; Toppari, Jorma; Knip, Mikael; Veijola, Riitta; Ilonen, Jorma; Lempainen, Johanna
Contributor organization: HUS Children and Adolescents
Children's Hospital
University of Helsinki
CAMM - Research Program for Clinical and Molecular Metabolism
Date: 2022-06-21
Language: eng
Number of pages: 9
Belongs to series: Frontiers in Immunology
ISSN: 1664-3224
DOI: https://doi.org/10.3389/fimmu.2022.909020
URI: http://hdl.handle.net/10138/346457
Abstract: 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 beta-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.
Subject: type 1 diabetes
autoantibodies
seroconversion
follow-up-cohort
survival analysis
AUTOANTIBODY APPEARANCE
SUSCEPTIBILITY LOCI
RISK
PROGRESSION
PTPN22
STAT4
ASSOCIATIONS
PREDICTION
VARIANTS
CHILDREN
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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