A1 Refereed original research article in a scientific journal
The effect of type 1 diabetes protection and susceptibility associated HLA class II genotypes on DNA methylation in immune cells
Authors: Pahkuri, Sirpa; Katayama, Shintaro; Valta, Milla; Nygård, Lucas; Knip, Mikael; Kere, Juha; Ilonen, Jorma; Lempainen, Johanna; Finnish Pediatric Diabetes Register
Publisher: Wiley-Blackwell
Publication year: 2024
Journal: HLA
Journal name in source: HLA
Journal acronym: HLA
Article number: e15548
Volume: 103
Issue: 6
ISSN: 2059-2302
eISSN: 2059-2310
DOI: https://doi.org/10.1111/tan.15548
Web address : https://doi.org/10.1111/tan.15548
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/456989571
The HLA region, especially HLA class I and II genes, which encode molecules for antigen presentation to T cells, plays a major role in the predisposition to autoimmune disorders. To clarify the mechanisms behind this association, we examined genome-wide DNA methylation by microarrays to cover over 850,000 CpG sites in the CD4+ T cells and CD19+ B cells of healthy subjects homozygous either for DRB1*15-DQA1*01-DQB1*06:02 (DR2-DQ6, n = 14), associated with a strongly decreased T1D risk, DRB1*03-DQA1*05-DQB1*02 (DR3-DQ2, n = 19), or DRB1*04:01-DQA1*03-DQB1*03:02 (DR4-DQ8, n = 17), associated with a moderately increased T1D risk. In total, we discovered 14 differentially methylated CpG probes, of which 10 were located in the HLA region and six in the HLA-DRB1 locus. The main differences were between the protective genotype DR2-DQ6 and the risk genotypes DR3-DQ2 and DR4-DQ8, where the DR2-DQ6 group was hypomethylated compared to the other groups in all but four of the differentially methylated probes. The differences between the risk genotypes DR3-DQ2 and DR4-DQ8 were small. Our results indicate that HLA variants have few systemic effects on methylation and that their effect on autoimmunity is conveyed directly by HLA molecules, possibly by differences in expression levels or function.
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Funding information in the publication:
This work was funded by the Sigrid Jusélius Foundation, Päivikki and Sakari Sohlberg Foundation, the Finnish Medical Foundation and the Pediatric Research Foundation (Johanna Lempainen and Jorma Ilonen), and the Sigrid Jusélius Foundation, the Jane and Aatos Erkko Foundation, Medicinska Understödsföreningen Liv och Hälsa, the Swedish Research Council, and the Swedish Brain Foundation (Hjärnfonden) (Juha Kere).
