ICA+ Relatives with DQA1*0102/DQB1*0602 have Expected 0602 Sequence and DR Types

Greenbaum, Carla J.; Gaur, Lakshmi K.; Noble, Janelle A.

doi:10.1006/jaut.2001.0562

Cited by 8 publications

(4 citation statements)

References 22 publications

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“…As part of this screening process, the DPT-1 identified a large number of DQB1*0602-positive subjects. Using data from an initial 100 subjects, we previously confirmed by sequence analysis that these subjects were in fact DQB1*0602 [12] and reported that these relatives were much less likely to be confirmed positive for islet cell cytoplasmic autoantibodies (ICA), to have multiple antibodies, and to have low firstphase insulin release [1]. In this report, we extend our previous cross-sectional observations and present additional autoantibody and metabolic data that address the natural history of these two parameters in this population of subjects.…”

Section: Introductionmentioning

confidence: 85%

High frequency of abnormal glucose tolerance in DQA10102/DQB10602 relatives identified as part of the Diabetes Prevention Trial?Type 1 Diabetes

Greenbaum¹,

Eisenbarth

Atkinson

et al. 2004

Diabetologia

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Aims/hypothesis: Immunological and genetic markers can be used to assess risk of developing type 1 diabetes prior to the onset of clinical symptoms. Autoantibody-positive relatives of patients with type 1 diabetes are at increased risk for disease, while the presence of HLA DQA1*0102/DQB1*0602 is thought to confer protection. Using the unique population identified by the Diabetes Prevention Trial-Type Diabetes (DPT-1), our aim was to determine if these individuals were protected from type 1 diabetes. Methods: We described metabolic and immunological characteristics of islet cell cytoplasmic autoantibodies-positive relatives with DQB1*0602 identified as part of DPT-1. Results: We found that 32% of DQB1*0602-positive relatives identified through the DPT-1 had abnormalities of glucose tolerance despite the fact that only 19% had multiple type 1 diabetes-associated autoantibodies and only 13% had abnormal insulin secretion, markers typically associated with the disease. In addition, these markers were not associated with abnormal glucose tolerance. In contrast, the DQB1*0602-positive relatives had elevated fasting insulin (117±10 pmol/l) and homeostasis model assessment of insulin resistance (HOMA-R) (4.90±0.5) values, which are more commonly associated with type 2 diabetes. The later marker of insulin resistance was associated with glucose tolerance status. Conclusions/ interpretation: Our data indicate that DQA1*0102/ DQB1*0602 relatives identified through DPT-1 have a high frequency of abnormal glucose tolerance and a disease phenotype with characteristics of type 1 and type 2 diabetes. Thus, multiple pathways to abnormal glucose tolerance are present within families of these type 1 patients.

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Section: Introductionmentioning

confidence: 85%

High frequency of abnormal glucose tolerance in DQA10102/DQB10602 relatives identified as part of the Diabetes Prevention Trial?Type 1 Diabetes

Greenbaum¹,

Eisenbarth

Atkinson

et al. 2004

Diabetologia

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“…12,[34][35][36] We previously reported significant clustering and coclustering of islet and celiac autoimmunity in the kindred, explained in part by a common association with DR3-DQ2, which was present in all of 16 relatives with celiac autoimmunity. 37 Interestingly, the frequency of DR3-DQ5 was higher among relatives with celiac autoimmunity compared to unaffected relatives with DR3-DQ2 (0.19 vs 0.05 among DR3-DQ2 relatives with and without celiac autoimmunity), although the difference was not statistically significant (Po0.10) and there was no difference in the distribution of class II haplotypes between relatives with celiac disease and relatives with celiac-related autoantibodies without celiac disease.…”

Section: Differential Effects Of Dr and Dqmentioning

confidence: 96%

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity

et al. 2007

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Autoimmune diabetes shows extreme variation in age of onset and clinical presentation, although most studies have been done in children with the most severe subtype. Disease risk is strongly associated with HLA-DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2), but it has not been possible to separate the effects of the DR and DQ alleles. We have identified a large Bedouin kindred in which a high prevalence of islet autoimmunity is associated with two different DR3 haplotypes, one carrying the usual DQ2 and the other carrying DQA1*0102-DQB1*0502 (DQ5). Results of prospective follow-up studies indicate that DR3 is associated with the initial activation of islet autoimmunity whereas DQ2 is associated with early-onset and severe clinical disease. The association signals map to a 350-kb interval, thus implicating primary effects for DR3 and DQ2. Overall, our results emphasize the importance of prospective genetic studies that examine the full range of variation in the initiation, progression and expression of autoimmune disease.

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“…Over 90% of Caucasian diabetic subjects possess one of susceptibility haplotypes HLA-DR4-DQA1*0301-DQB1*0302 or HLA-DR3-DQA1*0501-DQB1*0201 or both [23], [24], [25]. The HLA-DR15-DQA1*0102-DQB1*0602 haplotype is protective, and rarely present in T1D subjects [26], [27], [28]. As polymorphisms in the DR and DQ genes appear to be of great biological importance suggesting their involvement in the etiology of the disease [4], HLA class II genes are considered to be the best genetic markers for T1D [29] currently available.…”

Section: Introductionmentioning

confidence: 99%

Interaction between Treg Apoptosis Pathways, Treg Function and HLA Risk Evolves during Type 1 Diabetes Pathogenesis

Glišić

Jailwala

2012

PLoS ONE

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We have previously reported increased apoptosis of regulatory T cells (Tregs) in recent-onset Type 1 Diabetes subjects (RO T1D) in the honeymoon phase and in multiple autoantibody-positive (Ab+) subjects, some of which are developing T1D. We have also reported that increased Treg apoptosis was associated with High HLA risk and that it subsided with cessation of honeymoon period. In this report, we present results generated using genetics, genomics, functional cell-based assays and flow cytometry to assess cellular changes at the T-cell level during T1D pathogenesis. We measured ex vivo Treg apoptosis and Treg function, surface markers expression, expression of HLA class II genes, the influence of HLA risk on Treg apoptosis and function, and evaluated contribution of genes reported to be involved in the apoptosis process. This integrated comprehensive approach uncovered important information that can serve as a basis for future studies aimed to modulate Treg cell responsiveness to apoptotic signals in autoimmunity. For example, T1D will progress in those subjects where increased Treg apoptosis is accompanied with decreased Treg function. Furthermore, Tregs from High HLA risk healthy controls had increased Treg apoptosis levels and overexpressed FADD but not Fas/FasL. Tregs from RO T1D subjects in the honeymoon phase were primarily dying through withdrawal of growth hormones with contribution of oxidative stress, mitochondrial apoptotic pathways, and employment of TNF-receptor family members. Ab+ subjects, however, expressed high inflammation level, which probably contributed to Treg apoptosis, although other apoptotic pathways were also activated: withdrawal of growth hormones, oxidative stress, mitochondrial apoptosis and Fas/FasL apoptotic pathways. The value of these results lie in potentially different preventive treatment subjects would receive depending on disease progression stage when treated.

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ICA+ Relatives with DQA10102/DQB10602 have Expected 0602 Sequence and DR Types

Cited by 8 publications

References 22 publications

High frequency of abnormal glucose tolerance in DQA10102/DQB10602 relatives identified as part of the Diabetes Prevention Trial?Type 1 Diabetes

High frequency of abnormal glucose tolerance in DQA10102/DQB10602 relatives identified as part of the Diabetes Prevention Trial?Type 1 Diabetes

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity

Interaction between Treg Apoptosis Pathways, Treg Function and HLA Risk Evolves during Type 1 Diabetes Pathogenesis

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ICA+ Relatives with DQA1*0102/DQB1*0602 have Expected 0602 Sequence and DR Types

Cited by 8 publications

References 22 publications

High frequency of abnormal glucose tolerance in DQA1*0102/DQB1*0602 relatives identified as part of the Diabetes Prevention Trial?Type 1 Diabetes

High frequency of abnormal glucose tolerance in DQA1*0102/DQB1*0602 relatives identified as part of the Diabetes Prevention Trial?Type 1 Diabetes

Differential effects of DRB1*0301 and DQA1*0501-DQB1*0201 on the activation and progression of islet cell autoimmunity

Interaction between Treg Apoptosis Pathways, Treg Function and HLA Risk Evolves during Type 1 Diabetes Pathogenesis

Contact Info

Product

Resources

About

ICA+ Relatives with DQA10102/DQB10602 have Expected 0602 Sequence and DR Types

High frequency of abnormal glucose tolerance in DQA10102/DQB10602 relatives identified as part of the Diabetes Prevention Trial?Type 1 Diabetes

High frequency of abnormal glucose tolerance in DQA10102/DQB10602 relatives identified as part of the Diabetes Prevention Trial?Type 1 Diabetes

Differential effects of DRB10301 and DQA10501-DQB1*0201 on the activation and progression of islet cell autoimmunity