title: Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in siblings of affected children. Childhood Diabetes in Finland Study Group.
abstract: The relationships between genetic markers and disease-associated autoantibodies were studied in an unselected population of 701 siblings of children with type 1 diabetes, and the predictive characteristics of these markers over a period of 9 years were determined. Increased prevalences of all the antibodies were closely associated with HLA identity to the index case, the DR4 and DQB1*0302 alleles, and the DR3/4 phenotype and the DQB1*02/0302 genotype. Antibodies to GAD (GADA) were also associated with the DR3 and DQB1*02 alleles. Siblings carrying the protective DR2 and DQB1*0602-3 alleles were characterized by lower frequencies of islet cell antibodies (ICA), antibodies to IA-2 (IA-2A), and GADA. Higher levels of ICA were related to HLA identity, the DR4 and DQB1*0302 alleles, and the susceptible DQB1 genotypes, while no significant differences were observed in the levels of IA-2A, GADA, or insulin autoantibodies among siblings with different HLA risk markers. The DR2 or DQB1*0602-3 alleles were not related to the levels of any antibody specificity. A combination of the genetic markers and autoantibodies increased the positive predictive values of all autoantibodies substantially, which may have clinical implications when evaluating the risk of developing type 1 diabetes at the individual level or when recruiting high-risk individuals for intervention trials. However, because such combinations also resulted in reduced sensitivity, autoantibodies alone rather than in combination with genetic markers are recommended as the first-line screening in siblings. Finally, not all siblings with a broad humoral autoimmune response or high-risk genetic markers present with type 1 diabetes, while some with a low genetic risk and weak initial signs of humoral autoimmunity may progress to disease.
authors.affiliation: Department of Pediatrics, University of Oulu, Finland. petri.kulmala@oulu.fi
authors.forename: P
authors.initials: P
authors.lastname: Kulmala
authors.forename: K
authors.initials: K
authors.lastname: Savola
authors.forename: H
authors.initials: H
authors.lastname: Reijonen
authors.forename: R
authors.initials: R
authors.lastname: Veijola
authors.forename: P
authors.initials: P
authors.lastname: Vähäsalo
authors.forename: J
authors.initials: J
authors.lastname: Karjalainen
authors.forename: E
authors.initials: E
authors.lastname: Tuomilehto-Wolf
authors.forename: J
authors.initials: J
authors.lastname: Ilonen
authors.forename: J
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: H K
authors.initials: HK
authors.lastname: Akerblom
authors.forename: M
authors.initials: M
authors.lastname: Knip
mesh_terms: D000483:Alleles; D000917:Antibody Formation; D001323:Autoantibodies / Q000032:analysis*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005544:Forecasting; D005819:Genetic Markers; D006680:HLA Antigens / Q000032:analysis; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D010641:Phenotype
chemical_list: D001323:Autoantibodies; D005819:Genetic Markers; D006680:HLA Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens