Refereed journal article or data article (A1)

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




List of Authors: Laine Antti-Pekka, Valta Milla, Toppari Jorma, Knip Mikael, Veijola Riitta, Ilonen Jorma, Lempainen Johanna

Publisher: FRONTIERS MEDIA SA

Publication year: 2022

Journal: Frontiers in Immunology

Journal name in source: FRONTIERS IN IMMUNOLOGY

Journal acronym: FRONT IMMUNOL

Volume number: 13

Number of pages: 9

ISSN: 1664-3224

DOI: http://dx.doi.org/10.3389/fimmu.2022.909020

URL: https://www.frontiersin.org/articles/10.3389/fimmu.2022.909020/full

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/175968597


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.

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Last updated on 2022-17-08 at 11:16