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Background: Minnesota is home to the largest Somali population in USA, and pediatric diabetes teams are seeing increasing numbers of Somali children with diabetes.Objective: To assess the immune basis of diabetes in Somali children in the Twin Cities, Minnesota.Methods: A total of 31 Somali children <= 19 yr were treated for type 1 diabetes (T1D) at the University of Minnesota Masonic Children's Hospital and Children's Hospitals and Clinics of Minnesota underwent analysis of human leukocyte antigen (HLA) alleles (n=30) and diabetes autoantibodies [glutamic acid decarboxylase (GAD65), islet antigen 2 (IA-2), zinc transporter 8 (ZnT8); n=31]. HLA alleles were analyzed in 49 Somalis without diabetes (controls). Anti-transglutaminase autoantibodies (TGA) for celiac disease were also measured.Results: In Somali children with T1D aged 13.5 +/- 5 yr (35% female, disease duration 6.5 +/- 3.6 yr), the most common HLA allele was DRB1*03:01 (93%, compared with 45% of Somali controls), followed by DRB1*13:02 (27%). There was a relatively low frequency of DR4 (13%). Controls showed a similar pattern. All 31 participants were positive for at least one diabetes autoantibody. Insulin antibodies were positive in 84% (all were on insulin). Excluding insulin antibodies, 23 (74%) subjects tested positive for at least one other diabetes autoantibody; 32% had 1 autoantibody, 32% had 2 autoantibodies, and 10% had 3 autoantibodies. GAD65 autoantibodies were found in 56% of subjects, IA-2 in 29%, and ZnT8 in 26%. Four (13%) were TGA positive.Conclusion: The autoantibody and HLA profiles of Somali children with diabetes are consistent with autoimmune diabetes. Their HLA profile is unique with an exceptionally high prevalence of DRB1*03: 01 allele and relative paucity of DR4 alleles compared with African Americans with T1D.

The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from the development of type 1 diabetes (T1D). However, it is not known at which stages in the natural history of T1D development this haplotype affords protection. We examined a cohort of 3,358 autoantibody-positive relatives of T1D patients in the Pathway to Prevention (PTP) Study of the Type 1 Diabetes TrialNet. The PTP study examines risk factors for T1D and disease progression in relatives. HLA typing revealed that 155 relatives carried this protective haplotype. A comparison with 60 autoantibody-negative relatives suggested protection from autoantibody development. Moreover, the relatives with DRB1*15:01-DQA1*01:02-DQB1*06:02 less frequently expressed autoantibodies associated with higher T1D risk, were less likely to have multiple autoantibodies at baseline, and rarely converted from single to multiple autoantibody positivity on follow-up. These relatives also had lower frequencies of metabolic abnormalities at baseline and exhibited no overall metabolic worsening on follow-up. Ultimately, they had a very low 5-year cumulative incidence of T1D. In conclusion, the protective influence of DRB1*15:01-DQA1*01:02-DQB1*06:02 spans from autoantibody development through all stages of progression, and relatives with this allele only rarely develop T1D.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Diabetes is the most common comorbidity in individuals with cystic fibrosis. The etiology is poorly understood. Data on the presence of diabetes autoantibodies are conflicting, and little is known about type 1 diabetes gene associations. Our goal was to determine the prevalence of antibodies and HLA haplotypes known to be associated with type 1 diabetes in cystic fibrosis–related diabetes (CFRD). Patients with CFRD with fasting hyperglycemia were recruited from the University of Minnesota. Serum for antibodies and buffy coats for HLA were sent for analysis to the Barbara Davis Center for Childhood Diabetes (BDC). All patients gave informed consent. The Eisenbarth laboratory at BDC serves as the autoantibody/HLA reference laboratory for large national diabetes studies. Insulin, insulinoma-associated protein 2 (IA-2), GAD65, and zinc transporter 8 (ZnT8) autoantibodies were measured by radioimmunoassay …

BACKGROUND:Measurement of anti-islet autoantibodies at the time of disease onset contributes greatly to the differentiation of Type 1A diabetes with HLA Class II subtyping also contributing. METHODS:Blood samples were obtained from 900 patients with age from 1 month to 25 years (median age 11.1 years) within 2 weeks of diabetes onset to test anti-islet autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), insulinoma antigen (IA-2AA), the zinc transporter-8 (ZnT8AA), and islet-cell antibodies (ICA). Polymorphisms of the HLA Class II gene were typed in 547 randomly selected patients. RESULTS:Of the 900 subjects analyzed, 145 (16.1%) were negative for all five anti-islet autoantibodies, and autoantibody negativity significantly increased with age: 10.2% (38/372) among children <10 years of age, 14.2% (46/325) in those 10-14 years of age, and 30.1% (61/203) in those >14 years of age (P < 0.001). The prevalence of IA-2AA was the highest among young children. The prevalence of GADA increased with age while the prevalence of IAA was inversely correlated with age. At diagnosis, the subjects with negative antibodies had a higher body mass index (P < 0.001) and less high risk HLA genotype DR3-DQ2/DR4-DQ8 (P < 0.01). CONCLUSION:A large percentage of children and youths negative for all anti-islet autoantibodies at the onset of diabetes are likely to have the non-immune form, especially those without DR3/DR4 and obese patients. Among autoantibody-positive Type 1A patients, IAA and GADA showed a reciprocal prevalence, suggesting differential disease pathogenesis.

CONTEXT Autoimmune Addison's disease (AD) is the major cause of primary adrenal failure in developed nations. Autoantibodies to 21-hydroxylase (21OH-AA) are associated with increased risk of progression to AD. Highest genetic risk is associated with the Major Histocompatibility region (MHC), specifically human leukocyte antigen (HLA)-DR3 haplotypes (containing HLA-B8) and HLA-DR4. OBJECTIVE The objective of the study was the further characterization of AD risk associated with MHC alleles. DESIGN, SETTING, AND PARTICIPANTS MHC genotypes were determined for HLA-DRB1, DQA1, DQB1, MICA, HLA-B, and HLA-A in 168 total individuals with 21OH-AA (85 with AD at referral and 83 with positive 21OH-AA but without AD at referral). MAIN OUTCOME MEASURE(S) Genotype was evaluated in 21OH-AA-positive individuals. Outcomes were compared with general population controls and type 1 diabetes patients. RESULTS In HLA-DR4+ individuals, HLA-B15 was found in only one of 55 (2%) with AD vs. 24 of 63 (40%) 21OH-AA-positive nonprogressors (P = 2 × 10(-7)) and 518 of 1558 (33%) HLA-DR4 patients with type 1 diabetes (P = 1 × 10(-8)). On prospective follow-up, none of the HLA-B15-positive, 21-hydroxylase-positive individuals progressed to AD vs. 25% non-HLA-B15 autoantibody-positive individuals by life table analysis (P = 0.03). Single nucleotide polymorphism analysis revealed the HLA-DR/DQ region associated with risk and HLA-B15 were separated by multiple intervening single-nucleotide polymorphism haplotypes. CONCLUSIONS HLA-B15 is not associated with protection from 21OH-AA formation but is associated with protection from progression to AD in 21OH-AA-positive individuals. To our knowledge, this is one of the most dramatic examples of genetic disease suppression in individuals who already have developed autoantibodies and of novel dominant suppression of an autoimmune disease by a class I HLA allele.

Background:  We recently reported an association between Type 1 diabetes and the telomeric major histocompatibility complex (MHC) single nucleotide polymorphism (SNP) rs1233478. As further families have been analyzed in the Type 1 Diabetes Genetics Consortium (T1DGC), we tested replication of the association and, with more data, analyzed haplotypic associations.

OBJECTIVE The objective of this study was to test if the proportion of new-onset diabetic subjects with the HLA-DR3/4-DQB1*0302 genotype is decreasing over time. RESEARCH DESIGN AND METHODS We analyzed HLA class II genotype frequencies over time in two large populations with type 1 diabetes diagnosed at ≤18 years of age. There were 4,075 subjects from the Type 1 Diabetes Genetics Consortium (T1DGC) and 1,675 subjects from the Barbara Davis Center (BDC). RESULTS Both T1DGC and BDC cohorts showed a decrease of the highest-risk HLA-DR3/4-DQB1*0302 genotype over time. This decrease was greatest over time in T1DGC subjects with age of onset ≤5 years (P = 0.004) and onset between ages 6 and 10 years (P = 0.002). The overall percent of HLA-DR3/4-DQB1*0302 was greater in the T1DGC population compared with the BDC population. There was an increased percent over time of other HLA genotypes without HLA-DR3 or -DR4 in T1DGC new onsets (P = 0.003), and the trend was similar in BDC subjects (P = 0.08). Analyzing time trend, there appears to be a large stepwise decrease in percent DR3/4 in the 1980s in T1DGC subjects with onset age <5 years (P = 0.0001). CONCLUSIONS The change in frequency of multiple different genotypes and a possible stepwise decrease in percent DR3/4 suggest a change in genetic risk factors and environmental determinants of type 1 diabetes. Larger studies are needed to confirm the changing pattern of genetic risk because a stepwise change may have direct bearing on defining critical environmental determinants of type 1 diabetes.

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.

CONTEXT:There is controversy as to whether type 2 diabetes genetic susceptibility contributes to type 1 diabetes, and it is not known what proportion of islet autoantibody-negative new onset subjects have type 2 diabetes risk alleles. OBJECTIVES:We designed this study to evaluate whether two type 2 diabetes-associated single nucleotide polymorphisms (SNPs) of transcription factor 7-like 2 (TCF7L2) gene are associated with the development of islet autoantibody-negative diabetes vs. islet autoantibody-positive diabetes in young patients and whether these SNPs are associated with specific clinical phenotypes. DESIGN:Autoantibody against glutamic acid decarboxylase 65, islet cell antibody 512bdc (form of IA-2), insulin, ZnT8 transporter, and cytoplasmic islet cell antibody were assayed in patients with new onset diabetes seen at the Barbara Davis Center using sera obtained within 2 wk of diagnosis. We genotyped two noncoding variants in the TCF7L2 gene, rs12255372 and rs7903146, in diabetic subjects and normal controls. RESULTS:A total of 140 patients (15.7%) were negative for all islet autoantibodies among 893 subjects less than age 25 at the onset of diabetes. The allele and genotype frequencies of two SNPs showed that these are associated (odds ratio up to 4) with the development of diabetes in the autoantibody-negative diabetic cohort, but not in the autoantibody-positive diabetic cohort. CONCLUSION:TCF7L2 type 2 diabetes susceptibility alleles are associated with islet autoantibody-negative but not autoantibody-positive new onset diabetes in young patients.

A wealth of data in animal models indicates that type 1A diabetes results from T cell-mediated specific destruction of islet beta cells. There is evidence for the NOD mouse model that insulin is the primary autoantigen and a specific insulin peptide B:9-23 is central to pathogenesis. It is also now possible to predict the development of type 1A (immune mediated) diabetes for the great majority of individuals with a combination of genetic, immunological and metabolic parameters. Such prediction is possible because of the chronic nature of the autoimmunity and loss of beta cell function that precedes the disease. Given the ability to predict type 1A diabetes trials at all stages of the disorder to prevent beta cell destruction are now possible.

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.