Title: A population genetics analysis of the human T cell costimulatory locus in Type 1 diabetes
Description: Type 1 diabetes (T1D) is characterized by the loss of immune tolerance against insulin producing pancreatic beta cells, which are destroyed by an immuno-inflammatory process, resulting in elevated blood sugar and significant morbidity and mortality. T1D results from the complex interplay of genetic and environmental factors. In this work, our goal has been to delineate further the genetic susceptibility variants underlying T1D. For that purpose, we undertook a population genetics analysis of the human T cell costimulatory locus, where genes encoding CD28, CTLA-4 and ICOS reside within 300 kbps. These three molecules are key to controlling T cell activation, proliferation and terminal differentiation. Their juxtaposition in the genome lead to the intriguing idea that preferential combinations of genetic variants at the three genes might have been selected during human evolution. To test this hypothesis, we genotyped 22 single-nucleotide polymorphisms (SNPs) in 1064 individuals sampled from all over the World. The data showed the presence of extended haplotypes that encompass variants across the whole costimulatory locus. Some extended haplotypes reached up to 60% in some populations, and one of the major haplotypes identified bears all "protective" variants against T1D in Caucasians.

Since most of that work focused on common variants, we were interested in gauging the contribution of rare variants to T1D susceptibility. For that purpose, we sequenced CTLA4 in 565 T1D patients and a matched number of controls. The patterns of variation observed suggest that CTLA4 is under strong purifying selection, which prevents common SNPs from stabilizing. We found a single non-synonymous coding variant in a patient, which we are in the process of characterizing. In the last part of this work, we probed at which stage the currently described T1D susceptibility loci intervene. For that purpose, we genotyped 37 SNPs and reanalyzed HLA data collected prosectively in a large T1D prevention trial. The results indicate that the effect of most SNPs is present early in the disease process, since both autoantibody positive progressor and non-progressor individuals demonstrated skewed allele frequency at the candidate genes. Taken together, these data exemplify how population genetics can help understanding the genetics of autoimmune susceptibility loci.