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- Title
The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity.
- Authors
Hermann, Robert; Laine, A. P.; Veijola, R.; Vahlberg, T.; Simell, S.; Lähde, J.; Simell, O.; Knip, M.; Ilonen, J.
- Abstract
Aims/hypothesis: The aim of this study was to explore the contribution of genetic factors to the emergence of beta-cell-specific humoral autoimmunity. Subjects and methods: We analysed the effect of HLA class II, insulin (INS; -23 HphI variant) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4 [+49 and CT60]) genes on the appearance of beta-cell-specific autoantibodies in a large population-based birth cohort recruited in Finland. Infants carrying increased risk HLA DQB1 genotypes were monitored for the appearance of autoantibodies (islet cell autoantibodies [ICA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA] and islet antigen 2 antibodies [IA-2A]). Those who developed beta-cell-specific autoantibodies were studied (n=574, mean follow-up time: 4.9 years; range 0.5–9.3). Results: IAA emerged at a higher rate in children with the -23 HphI AA INS genotype than in those carrying AT or TT variants (hazard ratio 2.1, 95% CI 1.4–2.9, p«0.001). This effect of the INS locus was present in both HLA DQB1 risk groups. The appearance of IAA showed a strong association also with the HLA DRB1∗0401 allele (hazard ratio 13.1, 95% CI 1.8–93.4, p«0.001). The development of IA–2A was also somewhat accelerated by the DRB1∗0401 variant (p=0.03). Isolated ICA positivity was independent of the HLA and INS genotypes. None of the humoral immune markers showed association with the CTLA4 gene. Conclusions/interpretation: The INS and the DRB1 loci appear to contribute to the pathogenesis of type 1 diabetes by initiating/modifying insulin-specific autoimmunity. The emergence of IAA represents a crucial step in the development of beta cell autoimmunity in young children, in whom the appearance of GADA and IA–2A is linked to IAA.
- Subjects
HLA class II antigens; AUTOIMMUNE diseases; HLA histocompatibility antigens; AUTOIMMUNITY; IMMUNITY; IMMUNOLOGIC diseases
- Publication
Diabetologia, 2005, Vol 48, Issue 9, p1766
- ISSN
0012-186X
- Publication type
Article
- DOI
10.1007/s00125-005-1844-x