title: Influence of age on the associations among insulin autoantibodies, islet cell antibodies, and HLA DAQ1*0301-DQB1*0302 in siblings of patients with type 1 (insulin-dependent) diabetes mellitus. Belgian Diabetes Registry.
abstract: In recent-onset type 1 (insulin-dependent) diabetes mellitus (IDDM), insulin autoantibodies (IAA) and islet cell antibodies (ICA) occur preferentially in young (< 10 yr) patients with the HLA DQA1*0301-DQB1*0302 risk haplotype. We investigated whether this association also exists in siblings of IDDM patients. In our group of 310 siblings, aged 0-39 yr, 6% were positive for IAA, 7% for ICA 12 Juvenile Diabetes Foundation units (JDFU) or more, 5% for ICA 20 JDFU or more, and 2% for high titer ICA (> or = 80 JDFU). The occurrence of IAA and ICA (> or = 20 JDFU) was significantly associated, with a preferential relationship to the HLA DQA1*0301-DQB1*0302 susceptibility haplotype. In the present group of siblings, IAA and DQA1*0301-DQB1*0302 were significantly associated under age 10 yr (26% positivity for IAA vs. 4% in relatives without this haplotype). In this age group, IAA were more prevalent than (high titer) ICA (6%) in the presence of the haplotype. The association between (high titer) ICA and DQA1*0301-DQB1*0302 was not restricted to subjects under age 10 yr. High titer ICA (n = 5) occurred exclusively in homozygotes for the latter haplotype and in carriers of the heterozygous DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 high risk genotype, mostly under age 20 yr (four of five). The preferential occurrence of IAA in DQA1*0301-DQB1*0302-positive siblings under age 10 yr was caused by their high prevalence (47%) in subjects with the heterozygous high risk genotype in this age group. As in patients at onset, IAA and high titer ICA are preferentially associated with the DQA1*0301-DQB1*0302 haplotype in siblings of IDDM patients, but, unlike at onset, these associations are observed with specific genotypes only and are more pronounced in subjects under age 10 yr for IAA only. Longitudinal analysis in first degree relatives and other normal controls carrying the DQA1*0301-DQB1*0302 haplotype should assess the hypothesis that IAA qualify as earlier predictive markers for IDDM than high titer ICA.
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Belgium.
authors.forename: F K
authors.initials: FK
authors.lastname: Gorus
authors.forename: C L
authors.initials: CL
authors.lastname: Vandewalle
authors.forename: H
authors.initials: H
authors.lastname: Dorchy
authors.forename: P
authors.initials: P
authors.lastname: Van Crombrugge
authors.forename: F C
authors.initials: FC
authors.lastname: Schuit
authors.forename: D G
authors.initials: DG
authors.lastname: Pipeleers
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001323:Autoantibodies / Q000032:analysis*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics*; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007330:Insulin Antibodies / Q000032:analysis*; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male
chemical_list: D001323:Autoantibodies; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D007330:Insulin Antibodies; C024211:islet cell antibody