Children of parents with type 1 diabetes and prospectively followed from birth for the development of islet autoantibodies and diabetes were genotyped for single-nucleotide polymorphisms at 12 type 1 diabetes susceptibility genes (ERBB3, PTPN2, IFIH1, PTPN22, KIAA0350, CD25, CTLA4, SH2B3, IL2, IL18RAP, IL10 and COBL).
One is within the IL2RA gene for association with type 1 diabetes and the other in proximity with the CDKN2B gene for association with type 2 diabetes.
Here we apply PWAS ("proteome-wide analysis of SNPs"), a methodology based on quantitative mass spectrometry that enables rapid screening of SNPs for differential transcription factor binding, to 12 SNPs that are highly associated with type 1 diabetes at the IL2RA locus, encoding the interleukin-2 receptor CD25.
Interestingly, cesarean section appeared to interact with immune response genes, including CD25 and in particular the interferon-induced helicase 1 gene, where increased risk for type 1 diabetes was only seen in children who were delivered by cesarean section and had type 1 diabetes-susceptible IFIH1 genotypes (12-year risk, 9.1 vs. <3% for all other combinations; P < 0.0001).
Previous studies suggested the association of interleukin-2 (IL2) gene polymorphisms and its alpha- and beta-chain receptor (IL2RA and IL2RB) variants with different autoimmune diseases such as T1D, celiac disease, multiple sclerosis, and rheumatoid arthritis.
PTPN22 (1p13.2), STAT4 (2q32.2), CTLA4 (2q33.2), HLA (6p21), IL2RA (10p15.1), INS (11p15.5), ERBB3 (12q13.2), SH2B3 (12q24.12), and CLEC16A (16p13.13) were convincingly associated with autoimmune diabetes in adults (P ≤ 0.002), with consistent directions of effect as reported for pediatric type 1 diabetes.
Our observations confirm the presence of mRNA for pro- and anti-inflammatory cytokines in CD4+CD25+CD127dim/- cells in the peripheral blood of children with T1DM.
In conclusion, IL-2RA/CD25 is associated with type 1 diabetes in the Belgian population, independently of disease phenotype and other biologic markers.
Previous investigations have also demonstrated that two intronic SNPs (rs706778 and rs3118470) in the interleukin-2 receptor-alpha (IL2RA) gene were associated with type 1 diabetes in the Japanese population.
We further show that the inhibitory function is due to the induction of TGF-beta-producing CD4(+)CD25(-) islet-specific iTreg cells against the onset of T1D in NOD mice.
In addition, IL2RA genetic variants correlate with the levels of a soluble form of the IL-2 receptor in subjects with type 1 diabetes and multiple sclerosis.
These findings confirm and extend the association of this gene with MS and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between MS and T1D suggesting different immunopathological roles of IL2RA in these two diseases.
IL2RA/CD25, the gene for interleukin-2 receptor alpha, is emerging as a general susceptibility gene for autoimmune diseases because of its role in the development and function of regulatory T cells and the association of single-nucleotide polymorphisms (SNPs) within this gene with type 1 diabetes mellitus (DM), Graves' disease, rheumatoid arthritis (RA), and multiple sclerosis (MS).
We show that SLE is associated with rs11594656 (P = 3.87 x 10-7) and there is some evidence of association of rs41295061 with AAV (P = 0.0122), which both have prior association with T1D. rs2104286, an MS and T1D - associated SNP in the IL2RA locus, is not associated with either SLE or AAV.
Our study shows an association of HLA DQB1 genotypes with CD4+CD25+(high) T-cell apoptosis, which implicates CD4+CD25+(high) T-cell apoptosis as a new intermediate trait for T1D.
Here, we summarize what we know about the genetics of T1D with an emphasis on the contributions of mouse Il2 and human IL2RA polymorphisms and the IL-2-IL-2R pathway to autoimmunity and, more specifically, Treg development and function.
Here we use polychromatic flow cytometry to show that differences in surface expression of the human interleukin-2 (IL-2) receptor alpha (IL2RA, or CD25) protein are restricted to particular immune cell types and correlate with several haplotypes in the IL2RA region that have previously been associated with two autoimmune diseases, type 1 diabetes (T1D) and multiple sclerosis.
The present data confirm the type 1 diabetes association with IL2RA and provide evidence that the different contributions of the IL2RA in the susceptibility to acute-onset and other forms of type 1 diabetes in the Japanese population.
Here we use polychromatic flow cytometry to show that differences in surface expression of the human interleukin-2 (IL-2) receptor alpha (IL2RA, or CD25) protein are restricted to particular immune cell types and correlate with several haplotypes in the IL2RA region that have previously been associated with two autoimmune diseases, type 1 diabetes (T1D) and multiple sclerosis.