The effect of T1D-associated genetic polymorphisms on T cell subpopulations in children

Background

Multiple genetic factors associated with an elevated risk of type 1 diabetes (T1D) are thought to affect the development and maturation of immune cell subsets. T1D-associated polymorphisms may affect the function of the immune system by altering the frequency or phenotype of immune cell subsets. 

Methods

The subjects analysed in the study were participants in the Finnish DIPP (Diabetes Prediction and Prevention) study and the cohort comprised 86 subjects positive for at least one biochemical autoantibody, 75 subjects who had progressed to T1D and 231 autoantibody-negative control subjects. These children were screened for the presence of T1D-predisposing genotypes within the HLA region. Additionally seven T1D-associated single nucleotide polymorphisms in six non-HLA genes, INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243) and ERBB3 (rs2292239) were determined by qPCR. Several immune cell subset frequencies were analysed in blood samples by flow cytometry. The effects of the genetic markers on immune cell subset frequencies were assessed using analysis of covariance with the age of the children as a covariant.

Results

The most significant finding was the association of the PTPN22 rs2476601 risk allele with elevated total TREG (CD4+CD25+CD127-FOXP3+) frequencies (p < 0.001) and in particular naïve TREG (CD4+CD25+CD127-CD45RO+FOXP3+) frequencies (p < 0.001). These results remained significant when the clinically healthy subjects (p = 0.001) and children with T1D (p = 0.009 and p = 0.025 respectively) were analysed separately. These results will be validated in a separate cohort of healthy children with different PTPN22 rs2476601 genotypes.

Conclusions

Our results support the hypothesis that T1D-predisposing genetic polymorphisms affect T cell development and/or differentiation during childhood. Further studies are needed to clarify the mechanistic basis of these associations and their relevance for the pathogenesis of T1D.