A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus.

Khalil, I.; d'Auriol, L; Gobet, M; Morin, Laurence; Lepage, V.; Deschamps, I; Park, Min; Degos, Laurent; Galibert, Francis; Hors, J

doi:10.1172/jci114569

Cited by 326 publications

(204 citation statements)

References 21 publications

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“…However, a large number of healthy relatives have the susceptible genes. Additional genetic information therefore needs to be incorporated into a full model of genetic susceptibility, including characterization of both DQ-A and DQ-B chains [22]. In the present study, HLA identity did not expose relatives to an increased prevalence of autoantibodies and metabolic alterations.…”

Section: Discussionmentioning

confidence: 68%

“…The genetic background may therefore contribute to subclinical Beta-cell dysfunction which may progress in limited cases to clinical diabetes under the influence of immune and environmental factors. Recent molecular findings bring further insights into the genetic susceptibility to Type i diabetes [20][21][22]. However, a large number of healthy relatives have the susceptible genes.…”

Section: Discussionmentioning

confidence: 99%

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Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

et al. 1991

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Summary.Factors associated with diabetes onset were analysed for their predictive value in 708 first-degree relatives of Type 1 (insulin-dependent) diabetic patients including 374 parents and 308 siblings of Type i diabetic patients. Relatives were prospectively followed for 2 304 subject years with blood samples for specific autoantibody evaluation. Islet cell cytoplasmic autoantibody titres were quantified in Juvenile Diabetes Foundation units with a threshold of positivity of 5 units. Insulin autoantibodies were determined using Tyr-A14 iodinated human insulin. HLA typing was performed in 92% of the relatives. During the time of study, 17 of 646 (2.6%) relatives showed islet cell antibodies. During follow-up, eight relatives developed diabetes, including six with high islet cell antibody titre. Taking titres above 20 units increased the positive predictive value from 35% to 75% whereas the presence of insulin autoantibodies did not increase the positive predictive value for the disease. Analysis of metabolic profiles months before the onset of diabetes by either oral or intravenous glucose loads, indicated a considerable level of heterogeneity with relatives with a high islet cell antibody titre who rapidly developed insulin-dependent diabetes, whereas others remained insulin-independent during the same observation period despite comparable titres. This study clearly indicates that initial islet cell antibody titre is not sufficient to predict individual outcome. Follow-up samples are clearly needed to monitor progression of the disease. Few relatives with persistent immunologic positivity progress to clinical Type 1 diabetes, suggesting that non-progressive and sub-clinical Beta-cell dysfunction is common. Despite current knowledge and available genetic and immune markers, early identification of the relatives progressing to clinical diabetes is still difficult and does not allow at the present time aggressive immunointervention at the prediabetic stage.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

et al. 1991

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“…In addition, DLA DQA1 alleles coding for arginine at position 55 (Arg55) in hypervariable region 2 were associated with diabetes (Fig. 4) and might be equivalent to the association with HLA DQA1 Reactivity to canine GAD65 (counts per minute) Arg52 in human diabetes [48]. It is interesting to note that the 'increased-risk' haplotype is common in Samoyed dogs, the breed at greatest risk of developing diabetes.…”

Section: Insulin Deficiency Diabetesmentioning

confidence: 91%

Canine diabetes mellitus: can old dogs teach us new tricks?

et al. 2005

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“…However, an elegant study showed that DR4 haplotypes encoding both DRB*0401 (a subtype of DR4) and DQB*0302 were more diabetogenic than DR4 haplotypes encoding only one of these [53] ± thus, DRB1 and DQB1 together could confer susceptibility. The HLA-DQA1 locus also appears to be involved in susceptibility [54,55]. In addition to susceptibility alleles, there are also protective alleles.…”

Section: The Challenges Of Searching For Type I Diabetes Genesmentioning

confidence: 99%

Genetic linkage and association studies of Type I diabetes: challenges and rewards

Field

2002

Diabetologia

104

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Type I diabetes (formerly called insulin-dependent diabetes mellitus) results from the autoimmune destruction of the insulin-producing beta cells of the pancreas. It is now known that Type I diabetes is a genetically complex disease, i. e. a disease caused by multiple genes interacting with non-genetic (environmental and stochastic) factors. Family studies have clearly shown a genetic basis but inheritance of the disease does not follow a simple mendelian single-locus pattern. Population and family studies also suggest that most (perhaps all) affected individuals are genetically predisposed to Type I diabetes, particularly through HLA region genes. However, non-genetic factors appear to be required to precipitate the disease in these genetically susceptible persons because in monozygote (MZ) twin pairs in which one twin has Type I diabetes the MZ twin concordance rate is less than 100 %. It is not clear whether there are any purely genetic cases of Type I Diabetologia (2002) AbstractFamily and twin studies have shown clearly that Type I (insulin-dependent) diabetes mellitus has a genetic basis. However, only within the past decade has it been possible to systematically attempt to identify the genes that increase susceptibility to this disorder using linkage and association analysis of genetic markers distributed across the genome. More than 20 putative diabetes-predisposing genes have been localised in addition to HLA region susceptibility genes detected more than 25 years ago. Unfortunately, the effects of most diabetes-predisposing genes are weak, with the exception of HLA region susceptibility genes (which contribute about half of the genetic risk). The overall effects of diabetes-predisposing genes could be weak because the susceptibility gene occurs in only a small proportion of diabetic patients or the susceptibility gene (although it might be common) produces only a modest increase in risk, probably by acting in concert with other such genes to cause disease. The weak effects of these genes have made them difficult to locate, difficult to confirm in independent studies and difficult to isolate by genetic procedures. This paper summarizes the major challenges that have faced geneticists in mapping Type I diabetes genes, and reviews the progress achieved to date. The rewards of the genetic studies will be twofold: increased understanding of the causes of Type I diabetes, facilitating creation of preventative therapies, and enabling clinicians in the future to use genetic information to predict which children are predisposed to diabetes in order to target them for preventative therapies. [Diabetologia (2002) 45: 21±35]

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A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus.

Abstract: Family and population studies indicate that predisposition to insulin-dependent (

Cited by 326 publications

References 21 publications

Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

Canine diabetes mellitus: can old dogs teach us new tricks?

Genetic linkage and association studies of Type I diabetes: challenges and rewards

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