Genetic risk factors for type 1 diabetes.
Type 1 diabetes is diagnosed at the end of a prodrome of β-cell autoimmunity. The disease is most likely triggered at an early age by autoantibodies primarily directed against insulin or glutamic acid decarboxylase, or both, but rarely against islet antigen-2. After the initial appearance of one of these autoantibody biomarkers, a second, third, or fourth autoantibody against either islet antigen-2 or the ZnT8 transporter might also appear. The larger the number of β-cell autoantibody types, the greater the risk of rapid progression to clinical onset of diabetes. This association does not necessarily mean that the β-cell autoantibodies are pathogenic, but rather that they represent reproducible biomarkers of the pathogenesis. The primary risk factor for β-cell autoimmunity is genetic, mainly occurring in individuals with either HLA-DR3-DQ2 or HLA-DR4-DQ8 haplotypes, or both, but a trigger from the environment is generally needed. The pathogenesis can be divided into three stages: 1, appearance of β-cell autoimmunity, normoglycaemia, and no symptoms; 2, β-cell autoimmunity, dysglycaemia, and no symptoms; and 3, β-cell autoimmunity, dysglycaemia, and symptoms of diabetes. The genetic association with each one of the three stages can differ. Type 1 diabetes could serve as a disease model for organ-specific autoimmune disorders such as coeliac disease, thyroiditis, and Addison's disease, which show similar early markers of a prolonged disease process before clinical diagnosis.
Department of Pediatrics, Herlev and Gentofte Hospital, DK-2730 Herlev, Denmark.
Flemming
F
Pociot
Department of Clinical Sciences, Lund University, Skåne University Hospital, SE-20502 Malmö, Sweden. Electronic address: ake.lernmark@med.lu.se.
Åke
Å
Lernmark
D000293:Adolescent; D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D048909:Diabetes Complications / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015894:Genome, Human; D006680:HLA Antigens / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D050417:Insulin-Secreting Cells / Q000276:immunology; D008875:Middle Aged; D012313:RNA / Q000235:genetics; D012307:Risk Factors; D055815:Young Adult
D001323:Autoantibodies; D006680:HLA Antigens; D012313:RNA