We analyzed demographic and genetic differences between children with various diabetes-associated autoantibodies reflecting the autoimmune process. In a prospective birth cohort comprising children with HLA-conferred susceptibility to type 1 diabetes (T1D), the pattern of autoantibody appearance was analyzed in 520 children with advanced β-cell autoimmunity associated with high risk for disease. In 315 cases, a single biochemical autoantibody could be identified in the first positive sample as insulin (insulin autoantibody [IAA]) in 180, as GAD (GAD antibody [GADA]) in 107, and as IA-2 antigen (IA-2 antibody [IA-2A]) in 28. The age at seroconversion differed significantly between the three groups (P = 0.003). IAA as the first autoantibody showed a peak time of appearance during the second year of life, whereas GADA as the first autoantibody peaked later, between 3 and 5 years of age. The risk-associated insulin gene rs689 A/A genotypes were more frequent in children with IAA as the first autoantibody compared with the other children (P = 0.002). The primary autoantigen in the development of β-cell autoimmunity and T1D seems to strongly correlate with age and genetic factors, indicating heterogeneity in the initiation of the disease process.

Autoantibody patterns at diagnosis may be informative on primary autoantibodies initiating autoimmunity in young children developing type 1 diabetes.

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Several studies provide evidence that in addition to the DQ-DR genes, HLA contains another uncharacterized gene or genes associated with type 1 diabetes. Our aim was to investigate the effect of this gene independently of the DQ-DR genes and to localize it with a matched case-control study. More than 1,400 patients and 30,000 control individuals from Finland were studied. They were first genotyped for the selected alleles of the HLA-DQB1, -DQA1, and -DRB1 genes. For the DR3/4(0404) genotype, 75 patients and 181 control subjects were stratified, and 241 patients and 354 controls were stratified for the DR3/4(0401) genotype. Ten microsatellite markers in the HLA class III and I regions (D6S273, TNFa, C12A, STR MICA, MIB, C125, C143, C245, C3211, and MOGc) and selected alleles of the HLA-A and HLA-B genes were studied. In the DR3/4(0404)-stratified group, we found that markers located between C12A and C143 near the HLA-B gene confer a strong additional diabetes association. This was confirmed by the population differentiation test in both DR3/4(0404)-and DR3/4(0401)-stratified groups. Our data indicate that an additional gene associated with type 1 diabetes is located in the 240-kb region near HLA-B. We excluded STR MICA polymorphism as a mutation responsible for diabetes association. Diabetes 49:2217-2221, 2000 H LA localization of the genes predisposing to type 1 diabetes is well established. DQB1, DQA1, and DRB1 genes are considered primary and major loci associated with type 1 diabetes. However, evidence is accumulating that the HLA class I-III region contains gene(s) associated with an increased risk for type 1 diabetes (1-4) or its earlier age at onset (5-8). We searched for an additional HLA gene associated with type 1 diabetes among Finnish patients and control subjects stratified for the DQ-DR alleles.Initially, samples from >1,400 type 1 diabetic patients and >30,000 control subjects were collected and genotyped for DQB1 (9). DQB1*02/0302 subjects were then studied for the DQA1*05 and *0201 alleles and DR4 subtypes (of which only DRB1*0401 and DRB1*0404 are frequent among Finns). Thus, a group stratified for the DQA1*05-DQB1*02/ DQB1*0302-DRB1*0404 [DR3/4(0404)] genotype (75 patients and 181 control subjects) and a group stratified for the DQA1*05-DQB1*02/DQB1*0302-DRB1*0401 [DR3/4(0401)] genotype (241 patients and 354 control subjects) were selected. These subjects are all DR3/DR4 haplotype heterozygotes: one group carries DR404 and the other DR401 haplotype. Thus, within each group we excluded the diabetogenic effect of the known DQ-DR markers.In these groups, selected alleles of the HLA-B and HLA-A genes and 10 microsatellites (D6S273, TNFa, C12A, STR MICA, MIB, C125, C143, C245, C3211, and MOGc) were studied to map a non-class II HLA gene associated with type 1 diabetes susceptibility. These cover distance of ~2,300 kb and include the whole HLA class I region and the class I-III boundary (Fig. 1).We found that in the DR3/404-and DR3/401-stratified groups there was only one allele at each microsatellit...