Genetics of Type 1 Diabetes

Excerpt

Type 1 diabetes is a complex disease that has both genetic and environmental determinants. Based on twin and family studies from largely European-ancestry populations, the estimated contribution of genetic factors to type 1 diabetes risk is ~50%. Genes and their variants within the human major histocompatibility complex (MHC), the human leukocyte antigen (HLA) loci, including class I (HLA-A, -B, and -C) and class II (HLA-DR, -DQ, and -DP), account for ~50% of the genetic risk of type 1 diabetes. In addition to the MHC region, type 1 diabetes risk loci were initially identified through candidate gene and linkage studies, including variants in or near the INS, CTLA4, IL2RA, and PTPN22 genes. Genome-wide association approaches have revealed additional loci containing common variants with relatively small individual effects on type 1 diabetes risk. International efforts led by the Type 1 Diabetes Genetics Consortium and others have identified more than 90 non-MHC loci and narrowed the likely candidate genes and variants substantially through fine-mapping and functional studies. Ancestry-specific genetic associations of type 1 diabetes have emerged. The majority of non-MHC variants are in noncoding sequences and most likely affect gene regulation rather than directly altering protein structure. In addition to genetic factors, epigenetic changes in the genome are implicated in type 1 diabetes. Research on large cohorts of non-European ancestry, longitudinal follow-up of individuals in the preclinical stages of type 1 diabetes, and identification of the genetic and environmental underpinnings of distinct phenotypes that are emerging within the wide spectrum of type 1 diabetes are needed. Analytic and molecular studies to assess the functional significance of type 1 diabetes susceptibility gene variants would help identify critical biologic pathways that could lead to novel interventions and therapeutics.