title: Genetic modification of risk assessment based on staging of preclinical type 1 diabetes in siblings of affected children.
abstract: We set out to study the association between human leukocyte antigen-defined genetic disease susceptibility and the stage of preclinical type 1 diabetes and whether genetic predisposition affects the natural course of preclinical diabetes in initially nondiabetic siblings of affected children. A total of 701 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case: no prediabetes (no antibodies), early (one antibody specificity), advanced (two antibodies), and late prediabetes (three or more antibodies). Another classification system covering 659 siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to iv glucose: no prediabetes (no antibodies), early (one antibody specificity, normal FPIR), advanced (two or more antibodies, normal FPIR), and late prediabetes (at least one antibody, reduced FPIR). Genetic susceptibility to type 1 diabetes was defined by human leukocyte antigen identity and DR and DQ genotypes. There was a higher proportion of siblings with late prediabetes initially among those with strong genetic disease susceptibility than among those with decreased genetic predisposition (16.7% vs. 0.5%; P < 0.001 for DQB1 genotypes according to the first classification), whereas there was a higher proportion of siblings with no signs of prediabetes among those with genotypes conferring decreased risk (91.2% vs. 70.4% among those with high-risk DQB1 genotypes; P < 0.001 according to the first classification). Autoantibodies alone were more sensitive in the prediction of future diabetes in siblings than when combined with genetic susceptibility. Genetic susceptibility played a role in whether the initial prediabetic stage progressed (progression in 29.6% of the high-risk siblings compared with 6.6% of the siblings with DQB1 genotypes conferring decreased risk; P < 0.001 according to the first classification) and whether overt type 1 diabetes became manifest or not. Genetic susceptibility has an impact on both the initiation and progression of the autoimmune process leading to clinical diabetes in siblings of affected children.
authors.affiliation: Hospital for Children and Adolescents, University of Helsinki, FIN-00029 Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Mrena
authors.forename: K
authors.initials: K
authors.lastname: Savola
authors.forename: P
authors.initials: P
authors.lastname: Kulmala
authors.forename: H
authors.initials: H
authors.lastname: Reijonen
authors.forename: J
authors.initials: J
authors.lastname: Ilonen
authors.forename: H K
authors.initials: HK
authors.lastname: Akerblom
authors.forename: M
authors.initials: M
authors.lastname: Knip
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000008:administration & dosage; D006801:Humans; D007223:Infant; D007275:Injections, Intravenous; D007328:Insulin / Q000097:blood; D018570:Risk Assessment; D035781:Siblings; D013997:Time Factors
chemical_list: D001323:Autoantibodies; D007328:Insulin; D005947:Glucose