Genetics of Autoimmunity in Type 1 Diabetes

Abstract:  In the era of post-GWAS (Genome-Wide Association Studies), there is an urgent need to elucidate pathways behind the newly-found susceptibility variants in common, complex diseases. The effect of variants is often small and, even if combined, do not have a high positive predictive value (PPV) for disease. If we can identify an intermediate trait in disease-related cells, we should be able to implicate pathways as well as more accurately predict disease. This is because intermediate traits are influenced by both genetics and epigenetics, including environmental factors. We illustrate how this approach can work in Type 1 diabetes (T1D).

T1D is a T-cell-driven autoimmune, complex disease caused by multiple genetic and environmental risk factors. The HLA region on chromosome 6p comprising HLA-DRB1-DQB1 variants imparts the greatest susceptibility to T1D, even though several other loci, including interleukin 2 receptor alpha (IL-2RA or CD25, its protein product) and IL-2 have been implicated. T1D results in the destruction of insulinproducing, islet, beta cells. Both pathogenic effector T cells (T_EFFS) and protective (suppressive) regulatory T cells (T_REGS) infiltrate the islets (insulitis) during pathogenesis. T_REGS normally prevent T_EFFS from attacking beta cells.

We detected elevated apoptosis (>8% stained cells) in non-stimulated, polyclonal T_REGS from at-risk and recent-onset T1D subjects (recruited within 10 months from diagnosis). Apoptosis of T_REGS may lead to enhanced destruction of beta cells by T_EFFS. Whereas the maximum PPV for HLA-DRB1-DQB1 haplotypes is around 6%, our T_REGS apoptosis trait has a PPV of over 80%.

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Co-Sponsored by: Georgia Prevention Institute, MCG