title: Genetics of type 1 diabetes.
abstract: BACKGROUND
  Type 1 diabetes, a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic β cells. The major susceptibility locus maps to the HLA class II genes at 6p21, although more than 40 non-HLA susceptibility gene markers have been confirmed.
  
  
  BACKGROUND
  Although HLA class II alleles account for up to 30%-50% of genetic type 1 diabetes risk, multiple non-MHC loci contribute to disease risk with smaller effects. These include the insulin, PTPN22, CTLA4, IL2RA, IFIH1, and other recently discovered loci. Genomewide association studies performed with high-density single-nucleotide-polymorphism genotyping platforms have provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remain to be performed. Children born with the high-risk genotype HLADR3/4-DQ8 comprise almost 50% of children who develop antiislet autoimmunity by the age of 5 years. Genetic risk for type 1 diabetes can be further stratified by selection of children with susceptible genotypes at other diabetes genes, by selection of children with a multiple family history of diabetes, and/or by selection of relatives that are HLA identical to the proband.
  
  
  CONCLUSIONS
  Children with the HLA-risk genotypes DR3/4-DQ8 or DR4/DR4 who have a family history of type 1 diabetes have more than a 1 in 5 risk for developing islet autoantibodies during childhood, and children with the same HLA-risk genotype but no family history have approximately a 1 in 20 risk. Determining extreme genetic risk is a prerequisite for the implementation of primary prevention trials, which are now underway for relatives of individuals with type 1 diabetes.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO 80045-6511, USA. andrea.steck@ucdenver.edu
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Steck
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Rewers
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D001323:Autoantibodies; D005819:Genetic Markers; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II