Extreme genetic risk for type 1A diabetes in the post-genome era

A series of genes and loci influencing the genetic risk of type 1A (immune-mediated) diabetes are now well characterized. These include genes of the major histocompatibility complex (MHC), polymorphisms 5′ of the insulin gene, and PTPN22, as well as more recently defined loci from genome-wide association studies. By far the major determinants of risk for type 1A diabetes are genes within or linked to the MHC and in particular alleles of class II genes (HLA-DR, DQ, and DP). There is evidence that MHC class I alleles contribute and there are additional MHC-linked influences such that for a major subset of relatives of patients there is a risk as high as 80% for siblings, and for the general population a risk as high as 20% can be defined at birth just by analyzing the MHC. We believe the search for additional MHC loci will require analysis of the remarkable long-range identity (up to 9 million base pairs) of extended MHC haplotypes. Current prediction algorithms will likely be greatly improved for the general population when the additional contributing loci of the MHC are defined.