OBJECTIVE We sought to define the prevalence of nonislet, organ-specific autoantibodies at diagnosis of type 1 diabetes and to determine the prevalence of comorbid autoimmune diseases. RESEARCH DESIGN AND METHODS Children (n = 491) diagnosed with type 1 diabetes at the Barbara Davis Center for Childhood Diabetes were screened for autoimmune thyroid disease (thyroid peroxidase autoantibodies [TPOAb]), celiac disease (tissue transglutaminase autoantibodies [TTGAb]), and Addison disease (21-hydroxylase autoantibodies [21OHAb]). RESULTS Of the 491 children, 161 had at least one nonislet autoantibody, and of these, 122 (24.8%) were positive for TPOAb, and 15 of the 122 (12.3%) had autoimmune thyroid disease. There were 57 (11.6%) who were positive for TTGAb, of whom 14 (24.6%) had celiac disease. Five (1.0%) were positive for 21OHAb, of whom one had Addison disease. CONCLUSIONS Many autoantibody-positive subjects present with additional autoimmune disorders. Detection of these autoantibodies at type 1 diabetes onset may prevent complications associated with delayed diagnosis of these disorders.

OBJECTIVE: Upon diagnosis of type 1 diabetes, patients are usually symptomatic, and many have ketoacidosis. Screening for islet autoantibodies (IAs) has been shown to decrease A1C level and rate of hospitalization at diabetes onset. Metabolic tests and the presence of symptoms were described at diabetes onset during the Diabetes Prevention Trial–Type 1 (DPT-1). RESEARCH DESIGN AND METHODS: The DPT-1 screened relatives of patients with type 1 diabetes for islet cell autoantiobodies (ICAs). Those with positive ICAs had intravenous and oral glucose tolerance tests (IVGTTs and OGTTs) and were randomized into one of two prevention trials. Throughout the DPT-1 parenteral and oral insulin study, 246 people were diagnosed with type 1 diabetes. RESULTS: Of the 246 subjects diagnosed with diabetes, 218 had data regarding the presence of symptoms, and 138 (63.3%) reported no symptoms suggestive of diabetes. Eight subjects (3.67%) presented with ketosis. Subjects presented with a mean ± SD A1C of 6.41 ± 1.15%. At diagnosis, 90 subjects (50.8%) had A1C in the normal range (<6.2%). OGTT data at the time of diagnosis indicate that 35.4% had a glucose result of <100 mg/dl at 0 min. CONCLUSIONS: The majority of subjects diagnosed with type 1 diabetes through the DPT-1 were asymptomatic at onset and had normal fasting glucose and A1C levels. This suggests that intermittent screening (IA followed by OGTT) may allow diagnosis of diabetes before severe metabolic decompensation. Screening with A1C will miss identifying many of the subjects with newly diagnosed type 1 diabetes in this cohort.

OBJECTIVE—People with the HLA genotype DRB1*0301-DQA1*0501-DQB1*0201/DRB1*04-DQA1*0301-DQB1*0302 (DR3/4-DQ8) are at the highest risk of developing type 1 diabetes. We sought to find an inexpensive, rapid test to identify DR3/4-DQ8 subjects using two single nucleotide polymorphisms (SNPs). RESEARCH DESIGN AND METHODS—SNPs rs2040410 and rs7454108 were associated with DR3-DQB1*0201 and DR4-DQB1*0302. We correlated these SNPs with HLA genotypes and with publicly available data on 5,019 subjects from the Type 1 Diabetes Genetic Consortium (T1DGC). Additionally, we analyzed these SNPs in samples from 143 HLA-typed children who participated in the Diabetes Autoimmunity Study of the Young (DAISY) using Taqman probes (rs7454108) and restriction digest analysis (rs2040410). RESULTS—With a simple combinatorial rule, the SNPs of interest identified the presence or absence of the DR3/4-DQ8 genotype. A wide variety of genotypes were tested for both SNPs. In T1DGC samples, the two SNPs were 98.5% (1,173 of 1,191) sensitive and 99.7% (3,815 of 3,828) specific for DR3/4-DQ8. In the DAISY population, the test was 100% (69 of 69) sensitive and 100% (74 of 74) specific. Overall, the sensitivity and specificity for the test were 98.57 and 99.67%, respectively. CONCLUSIONS—A two-SNP screening test can identify the highest risk heterozygous genotype for type 1 diabetes in a time- and cost-effective manner.

OBJECTIVE There are variable reports of risk of concordance for progression to islet autoantibodies (Ab+) and type 1 diabetes in identical twins (IT) after one twin is diagnosed. We examined development of Ab+ and type 1 diabetes and the effects of genetic factors and common environment on Ab+ in IT, nonidentical twins (NT), and full siblings (FS). RESEARCH DESIGN AND METHODS Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for Ab+ (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these, 17,226 (157 IT, 283 NT, and 16,786 FS) were followed for Ab+ or type 1 diabetes for a median of 2.1 years. RESULTS At screening, IT were more likely to have positive GADA, IA-2A, and IAA than NT or FS (all P < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more Ab+, and two or more Ab+ (all P ≤ 0.03). Initially, Ab+ IT had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody negative (b−) IT. In NT, type 1 diabetes risk by 3 years was 72% for initially multiple Ab+, 13% for single Ab+, and 0% for initially Ab− NT. FS had a 3-year type 1 diabetes risk of 47% for multiple Ab+, 12% for single Ab+, and 0.5% for initially Ab− subjects. CONCLUSIONS Risk of type 1 diabetes at 3 years is high for initially multiple and single Ab+ IT and multiple Ab+ NT. Genetic predisposition, age, and male sex are significant risk factors for development of Ab+ in twins.

Context: Multiple autoimmune disorders (e.g. Addison’s disease, type 1 diabetes, celiac disease) are associated with HLA-DR3, but it is likely that alleles of additional genes in linkage disequilibrium with HLA-DRB1 contribute to disease. Objective: The objective of the study was to characterize major histocompatability complex (MHC) haplotypes conferring extreme risk for autoimmune Addison’s disease (AD). Design, Setting, and Participants: Eighty-six 21-hydroxylase autoantibody-positive, nonautoimmune polyendocrine syndrome type 1, Caucasian individuals collected from 1992 to 2009 with clinical AD from 68 families (12 multiplex and 56 simplex) were genotyped for HLA-DRB1, HLA-DQB1, MICA, HLA-B, and HLA-A as well as high density MHC single-nucleotide polymorphism (SNP) analysis for 34. Main Outcome Measures: AD and genotype were measured. Result: Ninety-seven percent of the multiplex individuals had both HLA-DR3 and HLA-B8 vs. 60% of simplex AD patients (P = 9.72 × 10⁻⁴) and 13% of general population controls (P = 3.00 × 10⁻¹⁹). The genotype DR3/DR4 with B8 was present in 85% of AD multiplex patients, 24% of simplex patients, and 1.5% of control individuals (P = 4.92 × 10⁻¹⁹¹). The DR3-B8 haplotype of AD patients had HLA-A1 less often (47%) than controls (81%, P = 7.00 × 10⁻⁵) and type 1 diabetes patients (73%, P = 1.93 × 10⁻³). Analysis of 1228 SNPs across the MHC for individuals with AD revealed a shorter conserved haplotype (3.8) with the loss of the extended conserved 3.8.1 haplotype approximately halfway between HLA-B and HLA-A. Conclusion: Extreme risk for AD, especially in multiplex families, is associated with haplotypic DR3 variants, in particular a portion (3.8) but not all of the conserved 3.8.1 haplotype.