Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Association of FOXP3 Polymorphisms with GAD65 Autoantibodies in Type 1 Diabetes  (#74)

Barbro Holm 1 , Eero Lindholm 2 , Kosrat Aziz 1 , Tina Uvebrant 1 , Christina Åkesson 1 , Carl-David Agardh 2 , Corrado M Cilio 1
  1. Cellular Autoimmunity Unit, Dept of Clinical Sciences, Lund University, Malmö, Sweden
  2. Dept of Clinical Sciences, Lund University, Malmö, Sweden

Type 1 diabetes (T1D) is a complex multifactorial organ-specific autoimmune disease under polygenic control. However, only a few candidate genes besides the MHC have been clearly proven to be associated with disease development.The human FOXP3is a forkhead transcription factor encoded by a gene on chromosome Xp11.23, which plays a crucial role in controlling self-tolerance. The involvement of FOXP3 in T1D has been previously suggested, although not fully elucidated yet.

We screened single nucleotide polymorphisms (SNPs) within the FOXP3 gene in 803 adult T1D patients and the SNPrs2232365 was correlated with various clinical parameters, including levels of GAD65 autoantibodies (GADA), HbA1c, fasting plasma glucose, fasting plasma C-peptide, body mass index (BMI) and HLA genotypes.

While no association to T1D was observed in a case control study, male patients with the minor A allele of SNPrs2232365 displayed lower frequencies of GADA (p=0.004) and lower GADA titers (p=0.003) compared to those with the G allele. When only male T1D patients with short disease duration (0 to 3 years) were considered, patients with the G allele had higher frequencies of undetectable C-peptide (30.3%) than those with the A allele (4.2%; p=0.02). When HLA genotypes were taken in account, a significant difference in the frequency of GADA positive individuals and GADA titers in the male T1D group with risk HLA-DQB1 genotypes was observed. Logistic regression analyses among all T1D males demonstrated that GADA were associated with shorter disease duration, older age, older age at onset of diabetes, HLA-DQB1 risk genotypes and with the FOXP3 rs2232365 G allele (p=0.0001).

These novel findings show that the minor A allele in the FOXP3 rs2232365 SNP might represent a protective factor in T1D pathogenesis and suggest a possible role of FOXP3 in the regulation of autoimmunity against pancreatic beta cell.