Type 1 diabetes (T1D), also known as ‘juvenile diabetes’, results from a self-destructive immune response against the insulin producing pancreatic b cells. As a result of this autoimmune response, patients lose the ability to secrete insulin and become dependent on insulin replacement therapy. Unfortunately, this form of treatment is often insufficient for natural control of insulin production to glucose, so a majority of T1D patients still succumb to a number of debilitating complications including blindness, kidney disease, amputation and heart disease.
Genomic approaches capture significant, but previously unrecognized, variability in a complex disease like T1D. The advent of genome-wide association studies (GWAS) has revealed an unexpected level of diversity in the loci that contribute to risk for most complex disorders, i.e., those having substantial contributions to risk from both genetic and environmental factors. T1D, which is a research focus within the CPHG, provides a good example. Our GWAS studies have identified more than 40 chromosomal regions (loci) that contribute to disease risk. Specific genes within these regions that are affected by causative variants are being fine mapped and defined, primarily through the development of a custom, 200,000-SNP genotyping array (ImmunoChip). The CPHG is currently genotyping over 75,000 samples on the ImmunoChip to identify candidate genes in the T1D loci for the purpose of targeted sequencing and functional studies. Similar approaches are being utilized for discovery of genes contributing to the complications of T1D.
These results create both an opportunity and a challenge for diabetes investigators. For many of the mapped chromosomal regions, the specific risk variants and genes have yet to be identified, creating an opportunity for further insights into disease pathogenesis through detailed genetic analyses. It is also clear that the mapped loci do not account for all of the genetic risk implied by familial aggregation of T1D. Thus, there are new opportunities for discovery of novel risk loci. At the same time, functional studies of T1D and other complex genetic disorders must now take into account variation at the recently mapped risk loci. Interpretation of results obtained in functional studies will require knowledge of the background genetics of cell lines utilized, and comparisons between biospecimens derived from different individuals will require genetic matching.