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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aetiology of Type I diabetes involves both genetic and environmental factors. The genes implicated are 'susceptibility genes', which modify risk. Individual susceptibility genes may not be required and are not sufficient for disease development. The strongest genetic risk component is encoded within the major histocompatibility complex (MHC) and is designated IDDM I. The HLA-DQ genes contribute to the risk, but so may other MHC-encoded genes. The susceptibility encoded by IDDM2 refers to a variable number of tandem repeats in the insulin gene region. Many other genomic regions have been designated as susceptibility intervals potentially containing candidate genes. Environmental factors appear to be important in disease expression in either a causative or a protective role. Epidemiological data indicate that such factors operate from early in life. Viral infection(s) may have a disease-initiating and/ or accelerating effect. A potential diabetogenic role for cows' milk protein remains unconfirmed. Further research is necessary to elucidate fully the aetiological factors involved and how they interact.
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PMID:The aetiology of Type I diabetes. 1076 62

The goal of this study is to assess the association of HLA-DQ alleles with the age of onset of type 1 diabetes in African American patients. Using PCR oligonucleotide typing, HLA-DQA1 and DQB1 alleles were determined. DQA1*0301, DQB1*0201, and DQB1*0302 were significantly increased in African American patients. However, the DQB1*0602 allele was decreased in these patients. In addition, DQA1*0401 and DQB1*0402, were associated with protection in African Americans. When stratified by age of onset, prepubertal patients showed an absence of the protective allele DQB1*0602 and a significant increase in DQB1*0201 compared to postpubertal patients. The high frequency of the HLA-DQ susceptibility allele in pre-pubertal patients suggest that the biology of disease in this group may differ from type 1 diabetes with a later age of onset.
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PMID:Early age of disease onset in African American type 1 diabetes patients is associated with DQB1*0201 allele. 1098 Mar 92

Geographical variations in the HLA-DQ genotypes associated with risk for type 1 diabetes were evaluated in Finland. Samples of 280 diabetic children diagnosed in Turku (south-west of the country) and 405 in Oulu (north of the country) were studied as well as a series of 14 096 and 10 016 newborns collected from the same hospitals. There were no major differences in the risk or protection conferred by various HLA-DQB1 genotypes between south-western and northern parts of the country when genotypes of children with type 1 diabetes from these two centres were compared with those of newborns, representing the background populations. However, the distribution of various genotypes was different, both in diabetic children and in newborns, when compared between the two regions (P < 0.0001, chi2 test). These differences reflected the allele frequencies in newborn cohorts in which HLA-DQB1*02 and DQB1*0301 were found more often in Turku and DQB1*0302 more often in Oulu (P < 0.0001 for all differences). Similar types of differences were detected when children who were diagnosed as having diabetes during the national 'Childhood Diabetes in Finland' (DiMe) study between the years 1986-1989 were compared according to their residence. The observed differences in genotype and allele frequencies demonstrate the heterogeneity for HLA alleles even in a population that is generally regarded as highly homogeneous. These differences also affect the sensitivity and efficiency of the screening programme used for identifying infants with genetic susceptibility to IDDM in the ongoing Finnish Diabetes Prediction and Prevention Study.
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PMID:Geographical differences within Finland in the frequency of HLA-DQ genotypes associated with type 1 diabetes susceptibility. The Childhood Diabetes in Finland Study Group. 1099 87

MHC class II molecules are critical determinants of genetic susceptibility to human type 1 diabetes. In patients, the most common haplotype contains the DRA1*0101-DRB1*0401 (DR4) and DQA1*0301-DQB1*0302 (DQ8) loci. To assess directly the relative roles of HLA-DQ8 and DR4 for diabetes development in vivo, we generated C57BL/6 transgenic mice that lack endogenous mouse MHC class II molecules but express HLA-DQ8 and/or DR4. Neither HLA-DQ nor HLA-DR transgenic mice developed insulitis or spontaneous diabetes. However, when they were crossed to transgenic mice (C57BL/6) expressing the B7.1 costimulatory molecules on pancreatic beta cells that do not normally develop diabetes, T cells from these double transgenic mice were no longer tolerant to islet autoantigens. The majority of DQ8/RIP-B7 mice developed spontaneous diabetes, whereas only 25% of DR4/RIP-B7 mice did so. Interestingly, when DQ8 and DR4 were coexpressed (DQ8DR4/RIP-B7), only 23% of these mice developed diabetes, an incidence indistinguishable from the DR4/RIP-B7 mice. T cells from both DR4/RIP-B7 and DQ8DR4/RIP-B7 mice, unlike those from DQ8/RIP-B7 mice, exhibited a Th2-like phenotype. Thus, the expression of DR4 appeared to downregulate DQ8-restricted autoreactive T cells in DQ8DR4/RIP-B7 mice. Our data suggest that although both DQ8 and DR4 can promote spontaneous diabetes in mice with a non-autoimmune-prone genetic background, the diabetogenic effect of the DQ8 allele is much greater, whereas DR4 expression downregulates the diabetogenic effect of DQ8, perhaps by enhancing Th2-like immune responses.
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PMID:The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model. 1128 96

HLA-DQ alleles are strongly associated with IDDM susceptibility and protection. Studies assessing the molecular properties of HLA-DR, a HLA class II locus in linkage disequilibrium with HLA-DQ, have made substantial contributions toward elucidating the structure and function of HLA class II molecules. Reports on the molecular properties of HLA-DQ are now following and have revealed interesting observations regarding the stability of HLA-DQ alphabeta heterodimers. Future work is expected to provide an understanding of the mechanism by which HLA-DQ is associated with IDDM susceptibility and protection.
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PMID:Molecular aspects of HLA class II alphabeta heterodimers associated with IDDM susceptibility and protection. 1132 97

Type 1 diabetes results from the destruction of the insulin-producing beta cells of the pancreas. The disease process is thought to be initiated by a complex interaction between genetic and environmental factors leading to a cellular and humoral autoimmune response against beta cell specific components. Over the past decade there has been important progress in identification of several diabetes specific autoantigens. The availability of recombinant antigens, most notably the enzyme glutamic acid decarboxylase (GAD) and the tyrosine phosphatase-like molecule IA-2, made it possible to develop simple, sensitive and specific radioimmunoassays for the detection of autoantibodies on a large scale. It has been shown that the combination of GAD antibodies (GADA) and IA-2 antibodies (IA-2-A) with insulin autoantibodies (IAA) can replace the conventional ICA test. This considerably facilitates screening programmes. Prospective studies in subjects with and without family history of type 1 diabetes conclusively demonstrate that the risk for type 1 diabetes is strongly correlated with the number of positive antibodies. The 5-10-years risk for type 1 diabetes varies from 0-1% in individuals with only one positive antibodies to 62-100% in subjects who were positive for three or more antibodies. Despite the identification of novel genetic markers associated with type 1 diabetes, the major histocompatibility complex, namely HLA-DQ alleles, still represents the strongest genetic risk factor. The analysis of HLA-DQ alleles may be important to discriminate between subjects at high or intermediate risk from antibody positive individuals carrying protective haplotypes. Assessment of the metabolic state using the first phase insulin response to intravenous glucose may provide additional information to predict rapid progression to diabetes. Screening for multiple antibodies is the most specific and sensitive strategy for identifying subject at risk for type 1 diabetes. Second-line genotyping or analysis of the first phase insulin response can serve as useful tool to improve the prediction of type 1 diabetes. The value of additional markers such as isotype specific autoantibodies or T-helper cells subsets measured by ELISPOT assays or FACS remains to be shown.
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PMID:Modern concepts for the prediction of type 1 diabetes. 1146 May 79

Type 1 diabetes mellitus is a T-cell-mediated autoimmune disease characterized by the selective destruction of pancreatic beta cells. Susceptibility to the disease is determined by a combination of genetic and environmental factors. The genetic factors are termed 'susceptibility genes' as they modify the risk of diabetes but are neither necessary nor sufficient for disease to develop. A large number of chromosomal regions have been identified as containing potential diabetes susceptibility genes. The IDDM1 locus, which encompasses the major histocompatibility complex on chromosome 6, is the major genetic risk factor. The HLA-DQ genes are the primary susceptibility genes within this region, although other genes may also contribute. The IDDM2 locus maps to a variable number of tandem repeats in the insulin gene region on chromosome 11. Further research is necessary to determine the precise location and identity of other diabetes susceptibility genes.
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PMID:Genetics of type 1 diabetes. 1155 71

The structural and functional properties of HLA-DQ and -DR molecules that confer susceptibility to several common autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis and multiple sclerosis, have been defined. The relevant polymorphisms directly affect interaction with peptides, which provides strong support for the hypothesis that these diseases are peptide-antigen driven. Several studies indicate that structural modifications of peptides can affect MHC class II binding and/or TCR recognition and should be considered in the analysis of T cell responses in autoimmune diseases.
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PMID:Insights into autoimmunity gained from structural analysis of MHC-peptide complexes. 1167 85

The autoimmune attack in type 1 diabetes is not only targeted to beta cells. We assessed the prevalence of thyroid peroxidase (aTPO), parietal cell (PCA), antiadrenal (AAA) and endomysial antibodies (EmA-IgA), and of overt autoimmune disease in type 1 diabetes, in relation to gender, age, duration of disease, age at onset, beta-cell antibody status (ICA, GADA, IA2A) and HLA-DQ type. Sera from 399 type 1 diabetic patients (M/F: 188/211; mean age: 26 +/- 16 years; duration: 9 +/- 8 years) were tested for ICA, PCA, AAA and EmA-IgA by indirect immunofluorescence, and for IA2A (tyrosine phosphatase antibodies), GADA (glutamic acid decarboxylase-65 antibodies) and aTPO by radiobinding assays. The prevalence rates were: GADA 70%; IA2A, 44%; ICA, 39%; aTPO, 22%; PCA, 18%; EmA-IgA, 2%; and AAA, 1%. aTPO status was determined by female gender (beta = - 1.15, P = 0.002), age (beta = 0.02, P = 0.01) and GADA + (beta = 1.06, P = 0.02), but not by HLA-DQ type or IA2A status. Dysthyroidism (P < 0.0001) was more frequent in aTPO + subjects. PCA status was determined by age (beta = 0.03, P = 0.002). We also observed an association between PCA + and GADA + (OR = 1.9, P = 0.049), aTPO + (OR = 1.9, P = 0.04) and HLA DQA1*0501-DQB1*0301 status (OR = 2.4, P = 0.045). Iron deficiency anaemia (OR = 3.0, P = 0.003) and pernicious anaemia (OR = 40, P < 0.0001) were more frequent in PCA + subjects. EmA-IgA + was linked to HLA DQA1*0501-DQB1*0201 + (OR = 7.5, P = 0.039), and coeliac disease was found in three patients. No patient had Addison's disease. In conclusion, GADA but not IA2A indicate the presence of thyrogastric autoimmunity in type 1 diabetes. aTPO have a female preponderance, PCA are weakly associated with HLA DQA1*0501-DQB1*0301 and EmA-IgA + with HLA DQA1*0501-DQB1*0201.
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PMID:Beta-cell, thyroid, gastric, adrenal and coeliac autoimmunity and HLA-DQ types in type 1 diabetes. 1170 58

An association has recently been described between increased birth weight and increased risk of childhood-onset type 1 diabetes. Whether this relationship is explained by genes associated with both increased birth weight and increased risk of type 1 diabetes is unknown. In the present study, we tested the association between birth weight and HLA-DQ genotypes known to confer risk for type 1 diabetes among 969 nondiabetic children randomly selected from the Norwegian population. We found that HLA genotypes previously shown to confer risk for type 1 diabetes were associated with reduced birth weight (the mean difference in birth weight between the DQB1*0602/DQB1*0602 and DQ8/DQ2 genotypes was 354 g [95% CI 105-604]), which was opposite of that expected if HLA genes explained the birth weight-type 1 diabetes association.
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PMID:Diabetes-associated HLA-DQ genes and birth weight. 1172 75


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