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

Using time-dependent methods, the temporal relationships between the detection of insulin and islet cell autoantibodies and the onset of insulin dependent diabetes (IDDM) were analyzed in a prospective study of 4694 nondiabetic relatives of 1929 patients with IDDM who had been followed for a median of 4 yr. Insulin autoantibodies were detected in 1.5% of relatives at their initial test whereas an additional 1.0% subsequently became positive for these antibodies during follow-up. Islet cell autoantibodies were detected in 2.6% of the relatives at the time of their first test and an additional 0.9% were observed to develop them during the follow-up period. The risk of developing IDDM was significantly higher (P = 0.0001) among those who were found to have one of these antibodies, but was highest among those under the age of 20 yr at inception of this study who tested positive for both. Among older relatives, the detection of insulin autoantibodies among those who were islet cell antibody positive did not convey an additional risk of IDDM. In a subset of relatives, the presence of either antibody was associated with a higher frequency (P < 0.001) of diabetes associated human leukocyte antigen-DR 3/4 heterozygotes. Islet cell autoantibodies were highly associated with elevated fasting and 60-min glucose concentrations (P = 0.0001) as well as decreased early phase (1 and 3 min) insulin response to an iv glucose tolerance test (P = 0.0001). Insulin antibodies were significantly associated with decreased early phase insulin response to iv glucose (P = 0.0003). These data confirm independent risks associated with each antibody and suggest that their temporal relationship may be an important reflection of the pathogenic process underlying IDDM observations which facilitate its predictability.
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PMID:Insulin and islet cell autoantibodies as time-dependent covariates in the development of insulin-dependent diabetes: a prospective study in relatives. 837 Jun 96

Target antigens defined by autoantibodies in IDDM include insulin, a putative glycolipid that reacts with islet cell antibodies, and a 64,000-M(r) protein recently identified as glutamic acid decarboxylase. In addition, some IDDM sera that contain antibodies to glutamic acid decarboxylase also coprecipitate a 38,000-M(r) protein from islets. This study used a high titer anti-38,000-M(r) serum to screen bacteriophage lambda cDNA expression libraries and identified human islet and placental clones encoding jun-B, the nuclear transcription protein, of predicted 38,000 M(r). Peripheral blood T-cells exhibited significant proliferation in response to a recombinant fragment of jun-B (amino acids 1-180) in 12 of 17 (71%) recent-onset IDDM subjects, 8 of 16 (50%) ICA-positive first-degree relatives of IDDM subjects who were at risk, 3 of 12 (25%) other autoimmune disease subjects, and 0 of 10 healthy control subjects. Proliferation to tetanus toxoid did not differ significantly between the groups. Responses to jun-B were not related to age, sex, or human leukocyte antigen status. Thus, autoreactive T-cells identify a novel antigen, p38 jun-B, in IDDM and appear to indicate subjects at risk for the development of clinical disease.
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PMID:Transcription factor jun-B is target of autoreactive T-cells in IDDM. 845 14

To examine the role of psychiatric diagnosis in the surgical outcome of pancreas transplantation, we studied candidates with type I diabetes mellitus. Eighty of 140 candidates underwent transplantation. Survival analysis found the extent of human leukocyte antigen-DR (HLA-DR) matching, two diagnoses, and patients' perceived support from first-degree relatives to be related to duration of full-graft function. Lifetime diagnoses of tobacco use disorder (P = 0.029) and alcohol abuse/dependence (P = 0.006) were associated with less favorable outcomes; perceived support was associated with positive outcomes (P = 0.048). Subsequent analysis suggested that the four variables independently and directly affect outcome.
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PMID:Psychiatric diagnosis and the surgical outcome of pancreas transplantation in patients with type I diabetes mellitus. 849 7

The polymorphic variable number of tandem repeats in the 5' upstream region of the human insulin gene is a well-known non-human leukocyte antigen locus contributing to genetic susceptibility to IDDM. Controversy exists about the question as to whether INS susceptibility haplotypes are or are not preferentially inherited together with HLA-DR4 haplotypes. We investigated whether genetic interaction between INS and the HLA complex can be better defined using DQ genotypic and phenotypic markers in addition to DR serology. The 5' INS 1/1 genotype was positively associated with IDDM both in non-DR4 subjects (relative risk = 4.3; 95% confidence interval, 1.6-11.5) and DR4 subjects (relative risk = 4.2; 95% confidence interval, 1.9-9.0). Further subdivision of IDDM patients and matched control subjects according to HLA-DQA1 and HLA-DQB1 genotype or phenotype also failed to show any association between 5' INS and HLA class II genes in diabetic patients. The 5' INS and HLA class II polymorphisms therefore provide independent risk markers, which may both contribute to the genetic screening of a high-risk population among nondiabetic individuals.
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PMID:5' insulin gene polymorphism confers risk to IDDM independently of HLA class II susceptibility. 849 8

To study the frequency of antibodies to glutamic acid decarboxylase (GAD65A) at the diagnosis of insulin-dependent diabetes mellitus (IDDM) and to evaluate the relation of these antibodies to other IDDM-associated autoantibodies and genetic risk markers of the disease, we analyzed 747 newly diagnosed diabetic children younger than 15 yr of age (mean, 8.4 yr) for GAD65A, islet cell antibodies, insulin autoantibodies, and human leukocyte antigen DR alleles. GAD65A were detected in 73.2% of the children, with a higher frequency in females than in males (77.1% vs. 70.1%; P = 0.04) and in index cases aged 10 yr or older than in younger children (79.0% vs. 68.7%; P = 0.004). The index cases positive for GAD65A had higher levels of islet cell antibodies (median, 40 vs. 34 Juvenile Diabetes Foundation units; P = 0.003) and insulin autoantibodies (median, 55 vs. 43 nU/mL; P = 0.03) than those testing negative for GAD65A. Human leukocyte antigen DR3/non-DR4 children had the highest GAD65A levels, whereas DR2-positive cases had levels of GAD65A similar to those found in other subjects. One third of the index cases (33.9%) tested positive for all three autoantibodies, 43.1% for two antibodies, and 18.2% for one antibody, whereas 4.8% were triple negative. The females had multiple antibodies (at least two antibodies) more often than the males (81.3% vs. 73.5%; P = 0.01). There was a significant trend for a higher frequency of multiple antibodies in young children (83.0% in those under 5 yr and 73.2% in those 10 yr or older; P = 0.02) and a higher frequency in DR3/4 heterozygous children than in those with DR3/non-DR4 (83.3% vs. 63.2%; P = 0.02). The results show that GAD65A antibodies are more frequent in girls and adolescents with newly diagnosed IDDM and suggest that DR3/non-DR4 subjects have increased GAD65A levels. Multiple antibodies in diabetic children are associated with young age, female sex, and DR3/4 heterozygosity.
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PMID:Glutamic acid decarboxylase antibodies in relation to other autoantibodies and genetic risk markers in children with newly diagnosed insulin-dependent diabetes. Childhood Diabetes in Finland Study Group. 867 60

The genetic susceptibility to Graves' disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves' disease, 293 patients with IDDM, and 325 controls. Patients with Graves' disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4). The phenotypic frequency of Ala-positive patients (73%) was significantly higher than of controls (58%; P = 10(-4); relative risk = 2). Patients with IDDM also had significantly more Ala alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In conclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' disease as well as to IDDM.
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PMID:CTLA4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus. 898 48

Elevated cellular immune responses against the cows' milk protein beta casein have been reported in individuals with Type I diabetes mellitus, a finding supportive of the concept that cows' milk consumption may be causative for the disease. We analysed cellular immune reactivities against beta casein in newly-diagnosed Type I diabetic patients, their immediate autoantibody negative relatives, and unrelated healthy individuals in order to further elucidate the role of anti-beta casein immunity in the pathogenesis of Type I diabetes mellitus. Peripheral blood mononuclear cells were stimulated in vitro with various concentrations of three different beta casein preparations, control antigens (tetanus toxoid, mumps extract) and a mitogen (phytohemagglutinin). The frequency and/or mean simulation index of cellular proliferation against two of the beta casein preparations at high antigen concentrations (i.e. 10 or 50 microg/ml) were significantly higher in newly-diagnosed Type I diabetic subjects compared with autoantibody negative healthy control subjects. However, reactivities against beta casein in the Type I diabetic probands and their autoantibody negative relatives, individuals with a very low-rate of disease development, were almost identical. Cellular immune reactivities to other antigens were similar between the subject groups. In addition to indicating the need for appropriately matched subject populations (e.g. human leukocyte antigen (HLA) matched relatives) when analysing cellular immune responses, these findings support our previous contention that individuals genetically prone to autoimmunity may be deficient in forming tolerance to dietary antigens. However, the significance of anti-beta casein immunity as a specific causative factor in the pathogenesis of Type I diabetes mellitus remains unclear.
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PMID:Cellular immune responses to beta casein: elevated in but not specific for individuals with Type I diabetes mellitus. 966 58

The human leukocyte antigen (HLA) complex, encompassing 3.5 Mb of DNA from the centromeric HLA-DPB2 locus to the telomeric HLA-F locus on chromosome 6p21, encodes a major part of the genetic predisposition to develop type 1 diabetes, designated "IDDM1." A primary role for allelic variation of the class II HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci has been established. However, studies of animals and humans have indicated that other, unmapped, major histocompatibility complex (MHC)-linked genes are participating in IDDM1. The strong linkage disequilibrium between genes in this complex makes mapping a difficult task. In the present paper, we report on the approach we have devised to circumvent the confounding effects of disequilibrium between class II alleles and alleles at other MHC loci. We have scanned 12 Mb of the MHC and flanking chromosome regions with microsatellite polymorphisms and analyzed the transmission of these marker alleles to diabetic probands from parents who were homozygous for the alleles of the HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes. Our analysis, using three independent family sets, suggests the presence of an additional type I diabetes gene (or genes). This approach is useful for the analysis of other loci linked to common diseases, to verify if a candidate polymorphism can explain all of the association of a region or if the association is due to two or more loci in linkage disequilibrium with each other.
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PMID:The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene. 1073 75

Major genetic susceptibility to type 1 diabetes mellitus maps to the human leukocyte antigen (HLA) region on chromosome 6p. During evolution, endogenous retroviral long terminal repeats (LTR) have been integrated at several sites within this region. We analyzed the presence of a solitary HERV-K LTR in the HLA DQ region (DQ-LTR3) and its linkage to DRB1, DQA1, and DQB1 haplotypes derived from 246 German and Belgian families with a patient suffering from type 1 diabetes mellitus. Segregation analysis of 984 HLA DQA1/B1 haplotypes showed that DQ-LTR3 is linked to distinct DQA1 and DQB1 haplotypes but is absent in others. The presence of DQ-LTR3 on HLA DQB1*0302 haplotypes was preferentially transmitted to patients from heterozygous parents (82%; P < 10(-6)), in contrast to only 2 of 7 DQB1*0302 haplotypes without DQ-LTR3. Also, the extended HLA DRB1*0401, DQB1*0302 DQ-LTR3-positive haplotypes were preferentially transmitted (84%; P < 10(-6)) compared with 1 of 6 DR-DQ matched DQ-LTR3 negative haplotypes. DQ-LTR3 is missing on most DQB1*0201 haplotypes, and those LTR3 negative haplotypes were also preferentially transmitted to patients (80%; P < 10(-6)), whereas DQB1*0201 DQ-LTR3-positive haplotypes were less often transmitted to patients (36%). Other DQA1/B1 haplotypes did not differ for DQ-LTR3 between transmitted and nontransmitted haplotypes. Thus, the presence of DQLTR3 on HLA DQB1*0302 and its absence on DQB1*0201 haplotypes are independent genetic risk markers for type 1 diabetes.
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PMID:The presence or absence of a retroviral long terminal repeat influences the genetic risk for type 1 diabetes conferred by human leukocyte antigen DQ haplotypes. Belgian Diabetes Registry. 1019 86

The human leukocyte antigen (HLA)-DQA1*0102/DQB1*0602/DRB1*1501 (DR2) haplotype confers strong protection from type 1 diabetes. Growing evidence suggests that such protection may be mostly encoded by the DQB1*0602 allele, and we reported that even first degree relatives with islet cell antibodies (ICA) have an extremely low diabetes risk if they carry DQB1*0602. Recently, novel variants of the DQB1*0602 and *0603 alleles were reported in four patients with type 1 diabetes originally typed as DQB1*0602 with conventional techniques. One inference from this observation is that DQB1*0602 may confer absolute protection and may never occur in type 1 diabetes. By this hypothesis, all patients typed as DQB1*0602 positive with conventional techniques should carry one of the above diabetes-permissive variants instead of the protective DQB1*0602. Such variants could also occur in ICA/DQB1*0602-positive relatives, with the implication that their diabetes risk could be significantly higher than previously estimated. We therefore sequenced the DQB1*0602 and DQA1*0102 alleles in all ICA/DQB1*0602-positive relatives (n = 8) previously described and in six rare patients with type 1 diabetes and DQB1*0602. We found that all relatives and patients carry the known DQB1*0602 and DQA1*0102 sequences, and none of them has the mtDNA A3243G mutation associated with late-onset diabetes in ICA-positive individuals. These findings suggest that diabetes-permissive DQB1*0602/3 variants may be very rare. Thus, although the protective effect associated with DQB1*0602 is extremely powerful, it is not absolute. Nonetheless, the development of diabetes in individuals with DQB1*0602 remains extremely unlikely, even in the presence of ICA, as confirmed by our further evaluation of ICA/DQB1*0602-positive relatives, none of whom has yet developed diabetes.
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PMID:Sequence analysis of the diabetes-protective human leukocyte antigen-DQB1*0602 allele in unaffected, islet cell antibody-positive first degree relatives and in rare patients with type 1 diabetes. 1032 7


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