Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While the human leukocyte antigen (HLA) region provides the major susceptibility for insulin-dependent (type I) diabetes mellitus (IDDM), other (non-HLA) genes must also play a role. Population studies have shown an increased frequency of small insertions (class I alleles) 5' to the insulin gene in individuals with IDDM, suggesting that this region may account for part, if not all, of the non-HLA genetic predisposition. However, no data are available as to whether the relation of the insulin gene polymorphism is to a DR-defined subset of IDDM or with all of IDDM. To test the hypothesis that specific combinations of HLA and insulin gene polymorphism alleles may interact in providing susceptibility for IDDM, HLA-DR and 5' insulin gene insertion size have been determined in 300 individuals with IDDM. The frequency of class 1 insulin gene alleles in the entire sample is 0.79 and the frequency of class 3 alleles (large inserts) is 0.20. The frequencies of class 1 alleles were equal across all DR classes: 0.79 in the DR3/X IDDM subjects, 0.80 in the DR4/X, 0.79 in the DR3/4, and 0.78 in those with DRX/X. Additionally, the frequencies of class 1/1 homozygotes and 1/3 heterozygotes were similar between HLA-DR types. These results suggest that the HLA region and the region 5' to the insulin gene provide independent and nonsynergistic genetic risks for IDDM.
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PMID:HLA-DR and the 5' insulin gene polymorphism in insulin-dependent diabetes. 196 Nov 15

Research in recent years has elucidated more clearly the genetic and immunopathogenic basis as well as the natural history of Type 1 diabetes mellitus. The development of Type 1 diabetes can be conceptually divided into stages, beginning in part with a human leukocyte antigen (HLA)-restricted genetic susceptibility. In some genetically susceptible subjects, a triggering event activates both cellular and humoral autoimmunity. Glucose-stimulated insulin secretion and beta cell mass diminish as anti-islet autoimmunity progresses. This process culminates in overt diabetes when only residual beta cell mass (estimated to be less than 10%) remains. Complete beta cell destruction follows within months to years of diagnosis. Most attempts at interrupting beta cell destruction have taken the form of broad immunosuppressive therapy begun at diagnosis when beta cell destruction is nearly complete. Greater understanding of early immune mediators and refinement of techniques to identify subjects at risk for Type 1 diabetes have set the stage for more specific immunomodulation targeted earlier in the course of the disease. We will review these recent advances in understanding the immunopathogenesis of Type 1 diabetes as they pertain to current and future trials of immunotherapy.
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PMID:Immunopathogenesis and immunotherapy of type 1 diabetes. 218 47

Almost all human leukocyte antigen (HLA) haplotypes positive for HLA-DR4 also carry the DQw3 specificity, which appears in one of two allelic forms, DQw3.1 or DQw3.2. Previous studies have shown that the frequency of the HLA DR4-DQw3.2 allele is approximately 95% among DR4-positive haplotypes of insulin-dependent diabetics (IDDM), but only 70% in DR4-positive haplotypes of unaffected individuals. Because this difference could be due to ethnic heterogeneity, it is important to establish whether the frequency of the DQw3.2 allele is also increased when haplotypes of diabetics are compared to those of "matched" unaffected individuals, as can be done within families. We have used the Genetic Analysis Workshop 5 (GAW5) data for this purpose. In every family, each parental DR4-bearing haplotype was categorized as "IDDM" if it appeared in any affected parent or offspring, or as "control" if not. When this was done, the frequencies of the DQw3.2 and 3.1 allele in 80 IDDM haplotypes were 94% and 6% respectively but 67% and 33% in 15 control haplotypes. This difference between the two kinds of haplotypes is highly significant (P less than 0.005).
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PMID:HLA DR4-DQw3.1 and 3.2 haplotypes among insulin-dependent diabetics and their unaffected sibs in the GAW5 data. 256 53

The classical sib pair method uses the expected and observed HLA (human leukocyte antigen) haplotype sharing distribution in sib pairs, who are affected with an HLA associated disease, to make inferences about the inheritance of the disease. In this paper we present the expected HLA haplotype sharing distributions in affected sib trios, and sib pairs, from families with three or more affected sibs. The underlying model for both distributions, as for the classical sib pair method, is that disease predisposition is determined by a single allele at an HLA-linked locus. The sib trio tests of hypotheses (additive and recessive), and disease parameter estimates (additive, recessive and intermediate), can be compared with those obtained from the classical sib pair analysis. In addition, the sib trio data allow parameter estimation for a general disease model to be made, if the data fall within the bounds of the expectation. This study forms the basis of later investigations which show that haplotype sharing of affected sib trios for two susceptibility alleles (negative complementation) model, which appears appropriate for insulin dependent diabetes mellitus (IDDM), moves outside the bound of the single susceptibility expectations outlined here, whereas haplotype sharing values for sib pairs are bound by the single susceptibility allele expectations. Available Caucasian IDDM data have been analysed. The results support genetic heterogeneity of IDDM.
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PMID:The affected sib method. IV. Sib trios. 386 24

In 5 patients (2 women and 3 men, aged 16-36 years), diabetic ketoacidosis developed without precipitating illness. Pancreatic islet cell antibody was negative, and the duration of insulin dependency was shorter than 4 weeks. Hemoglobin A1c was < or = 6.3% for the mean period of 2.8 years thereafter, with diet therapy alone in 4 and with 5 mg glyburide in 1. Four were overweight before the development of diabetes, and 3 of them positive for family history of adult-onset, non-ketotic diabetes. Frequency of human leukocyte antigen B61 was increased significantly in the patients. In a patient not previously overweight, family history of diabetes was negative, and human leukocyte antigen haplotypes common in insulin-dependent diabetes mellitus were accumulated. Serum immunoreactive insulin was within normal range or supranormal with normal glucose tolerance after recovery. The patients closely resemble black Americans with ketoacidosis-onset non-insulin dependent diabetes.
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PMID:Ketoacidosis-onset noninsulin dependent diabetes in Japanese subjects. 748 23

Because particular human leukocyte antigen (HLA) DQ alleles are the major predisposing factors for type 1 diabetes mellitus (IDDM), we investigated whether they are shared by other endocrine autoimmune diseases. We, therefore, analyzed the HLA DQ genotypes of 171 patients with IDDM, 271 with Graves' disease (GD), 65 with Hashimoto's thyroiditis, 51 with postpartum thyroiditis, 53 with Addison's disease (AD), and 271 healthy controls. HLA DQA1 and DQB1 alleles were defined by polymerase chain reaction and sequence-specific oligonucleotide hybridization as well as by single strand conformational polymorphism analysis. HLA DQA1*0501 was significantly more frequent in IDDM (60%), GD (65%), and AD (70%) than in controls (43%); DQA1*0301 was significantly more frequent only in IDDM (67% vs. 30% controls). The heterozygous state DQA1*0301/*0501 was found in 9% of controls and 35% of IDDM (relative risk, 5.6). An arginine at position 52 on either DQA1 allele was significantly more frequent in patients with IDDM (94%), GD (80%), and AD (89%) compared with controls (66%). HLA DQB1*0201 and DQB1*0302 were more frequent in IDDM patients (*0201, 62% vs. 36% in controls, *0302, 59% vs. 19% controls), whereas DQB1*0602 was less frequent in IDDM (4%) and GD (18% vs. 31% of controls). In conclusion, endocrine autoimmunity has a common immunogenetic background; susceptibility is conferred by DQA1*0501 as well as an arginine at position 52 of DQA1 alleles, and protection against IDDM and GD is conferred by DQB1*0602.
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PMID:Susceptibility and resistance alleles of human leukocyte antigen (HLA) DQA1 and HLA DQB1 are shared in endocrine autoimmune disease. 760 64

Islet cell antibodies (ICAs) are predictive markers of the disease in first-degree relatives of patients with insulin-dependent diabetes mellitus (IDDM). The large majority of newly diagnosed cases, however, will develop in children with no family history of diabetes. In France, the risk for development of IDDM up to the age of 20 years is 60 times higher in first-degree relatives than in the general population. The aim of this study was to test whether data collected in the first-degree relatives of IDDM patients could be transferred to children for the prediction of overt diabetes. A large population-based cohort of French school-aged children (n = 13,380; ages 6-17 years) were screened for ICAs, and results were compared with those of 1,185 first-degree relatives of IDDM patients. ICA prevalence rates were significantly different in the two populations (5.5% vs. 1.5%; P < 0.0001), with a significantly higher proportion of high ICA titers in first-degree relatives (37%) than in schoolchildren (14%) (P = 0.0005). ICA titers remained remarkably stable in children over 4 years. Insulin autoantibodies (IAAs) were found in 3.4 and 15.4% of ICA+ children and first-degree relatives, respectively. Susceptibility alleles at the human leukocyte antigen (HLA)-DQB1 locus were observed significantly more frequently in children in whom ICA titers > or = 20 Juvenile Diabetes Foundation units (JDF U) were found on two separate occasions (67%) than in ICA- children (52%) (P = 0.05). Five subjects developed overt diabetes during follow-up. ICA titers of > 20 JDF U were found in all of them on the first sample and at follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunogenetic determinants and prediction of IDDM in French schoolchildren. 765 24

We have postulated that a defect in specific antigenic induction of suppressor T lymphocytes may account for the immunoregulatory disorder in autoimmune thyroid disease. In this context, we have measured the proliferative responses of peripheral blood mononuclear cells (PBMC) to the synthetic peptides corresponding to the extracellular domain of the TSH receptor (TSHR) and recombinant glutamate decarboxylase (GAD65) by means of 3H thymidine incorporation. We have also studied the antigenic activation of CD4+ and CD8+ T lymphocytes by measuring human leukocyte antigen-DR (HLA-DR) expression on the cell surface by flow cytometric analysis. PBMC obtained from 47 patients with Graves' disease (GD) [including 19 hyperthyroid GD (hyper GD)], 18 with Hashimoto's thyroiditis (HT), 7 with nontoxic nodular goiter (NG), 18 with insulin-dependent diabetes (IDDM), and 20 normal controls (N), were cultured for 7 days in the presence or absence of the pool peptides representing 3 different segments of TSHR or GAD65 at final concentration of 30 micrograms/mL or 10 micrograms/mL. The proportion of subjects whose PBMC gave a positive proliferative response with a stimulation index (SI) of over 2.3 (i.e. above the mean +2 SD for N) to TSHR peptides was significantly higher in the hyper GD group than among euthyroid GD (eu GD), HT, IDDM, and N group. The corresponding differences in mean SI provided analogous results, showing significant responses above normal in only hyper GD. The CD4+ T lymphocytes from hyper GD group were significantly more activated by TSHR peptides compared to eu GD, HT, IDDM, and N, and this induction correlated to their thyroid hormone levels. Quite differently, the activation of CD8+ T lymphocytes from both hyper GD and eu GD group in response to TSHR peptides was impaired compared to HT, IDDM, and the N group; in contrast to the findings with CD4+ T lymphocytes, this was independent of thyroid hormone levels. On the other hand, while the CD8+ T lymphocytes from GD and N groups were activated equally by GAD65, the activation of CD8+ T lymphocytes from the IDDM group by GAD65 was impaired compared to the GD and N groups. In conclusion, the activation of CD8+ T lymphocytes from GD and IDDM by relevant antigens (i.e. TSHR peptides for GD and GAD65 for IDDM) was impaired, but not by irrelevant antigens (i.e. GAD65 for GD and TSHR peptides for IDDM). There was also a modest stimulation of CD8+ T cells from all groups by tetanus toxoid and cardiac myosin light chain peptide, both irrelevant antigens.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Activation of T lymphocyte subsets by synthetic TSH receptor peptides and recombinant glutamate decarboxylase in autoimmune thyroid disease and insulin-dependent diabetes. 771 99

The transporter associated with antigen processing (TAP) encoded in the major histocompatibility complex (MHC) class II region is a molecule required for endogenous antigen processing. We have typed TAP polymorphism in 95 Japanese patients with insulin-dependent diabetes mellitus (DDM) and 75 normal controls. Amino acid substitutions at positions 333 and 637 of TAP1 and at positions 379, 665, and 687 of TAP2 were typed by the polymerase chain reaction (PCR)-sequence-specific oligonucleotide method. In addition, DNA typing of human leukocyte antigen (HLA)-DQA1 and -DQB1 loci was performed by the PCR-restriction fragment length polymorphism method. There was no significant difference between IDDM patients and normal controls in the frequencies of TAP1 and TAP2 alleles. On the contrary, the HLA-DQ locus showed a strong association with IDDM in the same series of subjects. The frequencies of HLA-DQA1*0301 and -DQB1*0401 were increased significantly and those of HLA-DQA1*0103, -DQB1*0501, -DQB1*0601 and -DQB1*0602 were decreased significantly in Japanese IDDM patients compared with normal controls. Positive linkage disequilibrium was observed between HLA-DQB1*0303 and TAP2C and between HLA-DQB1*0401 and TAP2B. Negative linkage disequilibrium was observed between HLA-DQA1*0103 and TAP2A. Even when subjects with HLA-DQA1*0103, -DQA1*0301, -DQB1*0302, -DQB1*0303, and -DQB1*0401 were considered separately, no significant differences was found in the distribution of TAP1 and TAP2 alleles between IDDM patients and normal controls. We conclude that it is not TAP but HLA-DQ that exhibits a primary association with Japanese IDDM.
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PMID:Lack of association of the transporter associated with antigen processing with Japanese insulin-dependent diabetes mellitus. 805 40

A combination of immune, genetic, and metabolic markers potentially implicated in the development of insulin-dependent diabetes mellitus (IDDM) was studied in the general population. We screened 3,992 healthy schoolchildren, 12-18 years of age with no family history of IDDM, for islet cell antibodies (ICAs). Of the children, 69 (1.7%) were found to be ICA positive (ICA+), of whom 7 (0.17%) also were positive for insulin autoantibodies (IAAs). ICA+ children (group 1) were human leukocyte antigen (HLA) typed at the DQ locus along with 123 matched (group 2) and 235 random (group 3) control subjects (from the original cohort of 3,992). Of the ICA+ children, 28 underwent beta-cell function (beta-CF) studies. High-risk DQ types were surprisingly prevalent in all groups with 35.8% of random control subjects carrying DQB1*0302 and 8.9% carrying the highest risk HLA type for IDDM, DQB1*0302/*0201. Those individuals with higher ICA titer (> 19 Juvenile Diabetes Foundation units [JDF U]) had a significantly higher prevalence of DQB1*0302 than those with lower titer ICA or normal control subjects. Six of 7 individual positive for both ICA and IAA and typed at the DQ locus were DQB1*0302/*0201 heterozygotes or DQB1*0302 or DQB1*0201 homozygotes, representing three of the highest risk genotypes for IDDM. No correlation was observed between ICA titer or DQ type and beta-CF except that all those with beta-CF below the 5th percentile carried either DQB1*0302 or DQB1*0201. Prospective follow-up is underway to determine if any combination of DQ type and immune markers predicts decline in beta-CF and the development of IDDM.
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PMID:High genetic risk for IDDM in the Pacific Northwest. First report from the Washington State Diabetes Prediction Study. 826 22


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