Immunogenetics of type 1 diabetes: A comprehensive review

Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta cells in the pancreas. Prevention of T1D will require the ability to detect and modulate the autoimmune process before the clinical onset of disease. Genetic screening is a logical first step in identification of future patients to test prevention strategies. Susceptibility to T1D includes a strong genetic component, with the strongest risk attributable to genes that encode the classical Human Leukocyte Antigens (HLA). Other genetic loci, both immune and non-immune genes, contribute to T1D risk; however, the results of decades of small and large genetic linkage and association studies show clearly that the HLA genes confer the most disease risk and protection and can be used as part of a prediction strategy for T1D. Current predictive genetic models, based on HLA and other susceptibility loci, are effective in identifying the highest-risk individuals in populations of European descent. These models generally include screening for the HLA haplotypes “DR3” and “DR4.” However, genetic variation among racial and ethnic groups reduces the predictive value of current models that are based on low resolution HLA genotyping. Not all DR3 and DR4 haplotypes are high T1D risk; some versions, rare in Europeans but high frequency in other populations, are even T1D protective. More information is needed to create predictive models for non-European populations. Comparative studies among different populations are needed to complete the knowledge base for the genetics of T1D risk to enable the eventual development of screening and intervention strategies applicable to all individuals, tailored to their individual genetic background. This review summarizes the current understanding of the genetic basis of T1D susceptibility, focusing on genes of the immune system, with particular emphasis on the HLA genes.