Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental results and therapeutic strategies. Insulin-dependent diabetes mellitus (IDDM) results from an autoimmune aggression toward beta cells in genetically predisposed individuals. Examination of the frequency of the different antigens coded by the major histocompatibility complex reveals an increased proportion of DR3-DQ2 and DR4-DQ8 haplotypes in IDDM subjects. Sequencing DQ-beta chains in such patients indicates the absence of aspartate in position 57 when compared to control individuals. Islet cell cytoplasmic autoantibodies are early markers of ongoing autoimmunity in addition to insulin autoantibodies before administration of exogenous insulin. Experimental models of autoimmune diabetes like the NOD (NonObese Diabetes) mouse underline the predominant role of T lymphocytes in the constitution of both insulitis and beta cell destruction. In humans, an increased proportion of activated T lymphocytes can be observed but is not specific of the disease. This underlines the need for new cellular markers of the autoimmune process. Transgenic mice allow studies on the consequences of abnormal expression of new molecules on beta cell surface like cytokines or MHC class II molecules which represent a new field of investigation on the pathogenesis of IDDM. Prospective studies in first degree relatives of type I diabetic patients indicate the existence of an asymptomatic phase of beta cell destruction where specific autoimmune markers can be individualized. In some individuals abnormal insulin response to glucose--loss of first phase insulin release during intravenous glucose tolerance test--precedes insulin deficiency. The identification of an autoimmune process leading to beta cell destruction allows new therapeutic approaches with immunointervention at early stages of the disease.
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PMID:[Autoimmunity and insulin-dependent diabetes mellitus. Experimental data and therapeutic prospects]. 267 68

In Finland the haplotype A2, Cw1, B56, DR4, DQ8 is the third most common haplotype in insulin-dependent diabetic (IDDM) patients and has the highest haplotype-specific absolute risk for IDDM. Cw1, B56, DR4, DQ8 haplotypes containing HLA-A alleles other than A2 are infrequent in the population and are not associated with IDDM. Comparison of the A2 and non-A2 haplotypes at the DNA level showed that they were identical at HLA-B, -DR, and -DQ loci. Evidence that class I alleles confer susceptibility to IDDM was obtained from the two HLA-C, -B, -DR and -DQ haplotypes most frequently found in IDDM patients in Finland. A24, A3 and A2 on the Cw3, B62, DR4, DQ8 haplotype, and A28, A2 and A1 on the Cw7, B8, DR3, DQ2 were all found to be associated with IDDM. In Finland these seven haplotypes, including A2, Cw1, B56, DR4, DQ8, account for 33% of diabetic haplotypes and 10.3% of non-diabetic haplotypes (p < 0.00001). The contribution of the class I region to IDDM susceptibility was also apparent in those IDDM patients lacking the disease-predisposing class II alleles. Significantly more non-DR3/non-DR4 IDDM patients (47 of 55) possessed two of the IDDM-associated HLA-A alleles compared to non-DR3/non-DR4 control subjects (40 of 58; p = 0.038). Moreover, IDDM patients confirmed by oligotyping as unable to form a 'diabetes-susceptibility' DQ heterodimer, tended to possess two diabetes-associated HLA-A alleles (12 of 13) compared to control subjects (12 of 20; p = 0.056).
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PMID:A gene in the HLA class I region contributes to susceptibility to IDDM in the Finnish population. Childhood Diabetes in Finland (DiMe) Study Group. 767 3

HLA-DR2 is negatively associated with insulin-dependent diabetes mellitus (IDDM). The aim of the present study was to analyze DR2-positive patients among 425 consecutively diagnosed unrelated Swedish children with IDDM and in 367 matched controls. HLA-DRB, -DQA and -DQB were determined by Taq I restriction fragment length polymorphism analysis. Amplification by polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide probes was done for DQA1, DQB1 and DRB1 and DRB5. DR2 was positive in 11/425 patients (3%) and 101/367 (28%) controls (OR 0.07, p < 0.0001). Of the 11 DR2-positive patients, PCR was done in 10, of whom 8 were positive for DRB1*1601-DRB5*0201 compared to 4/96 (4%) controls (OR 92.0: p < 0.001) while the remaining 2 were positive for DRB1*1501-DRB5*0101 compared to 92/96 (96%, OR 0.01; p < 0.001). In 2 patients, a recombination between the haplotypes DQB1*0502-DQA1*0102 (DQ5)-DRB1*1601-DRB5*0201 (DR16 Dw21) and DQB1*0301-DQA1*0501 (DQ7)-DRB1*1602-DRB5*0202 (DR16 Dw22) was observed resulting in the DQB1*0301-DQA1*0501 (DQ7) DRB1*1601-DRB5*0201 (DR16 Dw22) haplotypes. The second haplotype was DR3 DQ2 in 6/11 and DR4 DQ8 in 2/11 DR2-positive patients. In all 3 DQB1*0602-DQA1*0102-DR15-positive patients the second haplotype was DR4-positive. In order to test whether physicochemical properties of the DR2 molecules were associated with IDDM, we constructed three-dimensional models of the peptide binding and T-cell recognition sites (alpha 1 and beta 1 domains) of five subtypes of DR2-DRB1, based on the published DR1 crystal structure. No correlations were observed for DR molecule physicochemical properties and diabetes susceptibility. Islet cell antibodies, insulin autoantibodies and GAD65 antibodies, were measured in DR2-positive patients (n = 11) and controls (n = 101). Despite the presence of the DR2 haplotype the antibody markers were significantly elevated in the patients compared to the controls (GAD65 3/10 patients and 2/101 controls; ICA 7/11 patients and 1/101 controls and IAA 3/11 patients and 0/101 controls). In conclusion, of the five subtypes of DR2, only one, the DRB1*1501, DRB5*0101, DQB1*0602-DQA1*0102 haplotype, was negatively associated with IDDM. DQ may therefore confer more protection from the disease than DR.
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PMID:Analysis of antibody markers, DRB1, DRB5, DQA1 and DQB1 genes and modeling of DR2 molecules in DR2-positive patients with insulin-dependent diabetes mellitus. 781 75

The clinical onset of insulin-dependent diabetes is associated with several autoimmune phenomena including islet cell antibodies, glutamic acid decarboxylase (the GAD65 isoform) autoantibodies (GAD65Ab) as well as insulin autoantibodies. The molecular cloning of these autoantigens has permitted the development of precise and reproducible antibody immunoassays to identify marker-positive patients and control subjects. Among patients with new-onset diabetes about 70% were GAD65Ab positive compared to 1.5% among control subjects while 46% of patients had IAA compared to 1% among control subjects. The autoreactive sites or epitopes of GAD65 and insulin remain to be determined. The disease association with HLA on chromosome 6 may help to define the epitope specificity of the autoimmune reaction. Recent data suggest that 95% of new-onset IDDM children (0-15 years of age) are positive for either DQ2, DQ8 or both compared to about 50% of healthy control subjects. HLA-DQ6 is negatively associated with the disease. Both HLA-DQ2 and DQ8 therefore seem to be necessary, but not sufficient for diabetes. Molecular modelling suggests comparable physicochemical properties of DQ2 and DQ8 but are widely different from DQ6. In 1984, the conclusion was that molecular cloning of the genes for the autoantigens, antibodies, T-cell receptors, as well as HLA class I and II molecules associated with diabetes are essential for analysing the components which control the development of pancreatic beta-cell autoimmunity. In 1994, autoantigens and HLA molecules have been cloned and recombinant reagents developed to be used in experiments aimed at testing whether it will be possible to predict IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular biology of IDDM. 782 43

Fifty juvenile insulin dependent diabetes mellitus (JIDDM) patients of Tamil Nadu (South India) were typed for HLA-A, -B, -C, -DR, and -DQ, ESD, GLOI, C3 and HP polymorphisms. The frequencies of B8, DR3, DR4, DR53 and DQ2 antigens of the HLA system were significantly higher in the patients than in controls (relative risk, RR = 4.81; 5.14; 3.98; 3.36 and 2.53, respectively). However HLA-DR2, -DR5 and -DQ1, observed less frequently in the patient group, appear to play a role of protection against the disease (RR = 0.32; 0.30 and 0.20 respectively). HLA haplotype analysis demonstrated very high relative risk associated with two hitherto unreported haplotypes namely A3,DR1 and Cw3,DR4 (RR = 27.30 and 20.00, respectively) and also scanty distribution of the haplotypes A1,B17 and DR2,DQ1 (RR = 0.39 and 0.36, respectively) in the patient group. Among other genetic markers tested, GLOI is informative with its phenotype GLOI 2-1 showing positive association with JIDDM (RR = 4.06).
Diabetes Res Clin Pract 1994 Aug
PMID:HLA, ESD, GLOI, C3 and HP polymorphisms and juvenile insulin dependent diabetes mellitus in Tamil Nadu (south India). 783 12

Peptide binding to DQ molecules has not previously been described. Here we report a biochemical peptide-binding assay specific for the DQ2 [i.e. DQ(alpha 1*0501, beta 1*0201)] molecule. This molecule was chosen since it shows a strong association to diseases such as celiac disease and insulin-dependent diabetes mellitus. Initially we radiolabelled some selected peptides and tested them for binding to affinity-purified DQ2 molecules. One of the peptides, a Mycobacterium bovis (MB) 65 kDa 243-255Y peptide, displayed a good signal-to-noise ratio and was thus chosen as an indicator peptide in the DQ2 binding assay. The MB 65 kDa 243-255Y peptide bound to DQ2 in a strictly pH-dependent fashion, with optimal binding around pH 5 and only weak binding at pH 7.4. The association of the MB 65 kDa 243-255Y peptide to DQ2 was slow, but once formed, the peptide-HLA complexes were very stable. The binding of peptides to DQ2 was specific, as shown in inhibition experiments with a panel of 47 peptides, differing in length, sequence, and origin. The binding of peptides to DR3 was tested in a similar assay with a Mycobacterium tuberculosis 65 kDa 3-13 peptide as the binding indicator. DQ2 and DR3 molecules bound to different sets of peptides. However, the peptide binding to DQ2 and DR3 showed, in general, similar characteristics with respect to pH dependence and kinetic parameters, indicating that the overall rules for peptide binding to DQ molecules are the same as those previously shown for human DR and murine I-A and I-E molecules.
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PMID:Binding of peptides to HLA-DQ molecules: peptide binding properties of the disease-associated HLA-DQ(alpha 1*0501, beta 1*0201) molecule. 818 96

The TAP1 and TAP2 genes, located in the HLA class II region, encode subunits of a peptide transporter. Both genes display limited genetic variability; four different nucleotide substitutions have been found in the TAP2 gene. Here studies on linkage disequilibrium between TAP2 variants and HLA class II alleles are reported, in an attempt to evaluate whether TAP2 variants are associated with insulin-dependent diabetes mellitus (IDDM). As reported previously, a significant decrease of homozygosity for TAP2 alleles encoding alanine at residue 665 (665 Ala) and glutamine at 687 (687 Gln) paralleled by an increase in homozygosity for TAP2 alleles encoding threonine at residue 665 (665 Thr) and a stop codon at 687 (687 Stop), was found in both Finnish and Norwegian IDDM patients compared to random controls. However, a strong linkage disequilibrium between these TAP2 polymorphisms and given HLA-DR and -DQ genes was observed among healthy controls. The frequent 665 Thr and 687 Stop variants were in linkage disequilibrium both with the DR4-DQ8 and the DR3-DQ2 haplotypes, haplotypes which are strongly associated with IDDM. In contrast, the DR1-DQ5 and DR13-DQ6 (e.g. DQB1*0603) haplotypes, which are decreased among IDDM patients, were associated with the 665 Ala and 687 Gln variants. Thus, when DR- and DQ-matched patients and controls were compared, associations of the investigated TAP2 variants and IDDM were no longer detectable. These data, therefore, indicate that the associations previously found between certain TAP2 variants and IDDM are secondary to a primary association between this disease and particular DQ alpha beta heterodimers.
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PMID:Linkage disequilibrium between TAP2 variants and HLA class II alleles; no primary association between TAP2 variants and insulin-dependent diabetes mellitus. 847 1

DQCAR is a very polymorphic CA repeat microsatellite located between the HLA DQA1 and DQB1 gene. Previous studies have shown that specific DQCAR alleles are in tight linkage disequilibrium with known HLA DR-DQ haplotypes. Of special interest was the fact that haplotypes containing long CA repeat alleles (DQCAR > 111) were generally more polymorphic within and across ethnic groups. In these latter cases, several DQCAR alleles were found even in haplotypes containing the same flanking DQA1 and DQB1 alleles. In this work, three HLA class II associated diseases were studied using the DQCAR microsatellite. The aim of this study was to test if DQCAR typing could distinguish haplotypes with the same DRB1, DQA1 and DQB1 alleles in control and affected individuals. To do so, patients with selected HLA DR-DQ susceptibility haplotypes were compared with HLA DR and DQ matched controls. This included: Norwegian subjects with Celiac disease and the HLA DRB1*0301, DQA1*05011, DQB1*02 haplotype; Japanese subjects with Type 1 (insulin-dependent) Diabetes Mellitus and the HLA DRB1*0405, DQA1*0302, DQB1*0401 haplotype; and French patients with corticosensitive Idiopathic Nephrotic Syndrome and the HLA DRB1*0701, DQA1*0201, DQB1*0202 haplotype. These specific haplotypes were selected from our earlier work to include one haplotype bearing a short DQCAR allele (celiac disease and DR3,DQ2-DQCAR99) and two haplotypes bearing long DQCAR alleles (Diabetes Mellitus and DR4,DQ4-DQCAR 113 or 115 Idiopathic Nephrotic syndrome and DR7,DQ2-DQCAR 111-121). Additional DQCAR diversity was found in both control and patients bearing haplotypes with long CA repeat alleles. The results indicate that DQCAR typing did not improve specificity in combination with high resolution DNA HLA typing as a marker for these three disorders.
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PMID:DQCAR microsatellite polymorphisms in three selected HLA class II-associated diseases. 856 Apr 48

Celiac disease (CD) is an immune disease triggered by the cereal antigen gliadin, resulting in villous atrophy in the small intestine. Susceptibility to the development of CD is strongly influenced by genes in the major histocompatibility complex, in particular alleles of the DQ genes in the class II region. However recent evidence has suggested that the major histocompatibility complex (MHC) class III region may be linked to celiac disease independently of the class II region. Among the genes located in this area is TNF-alpha, which encodes the cytokine tumor necrosis factor-alpha which has a broad range of pro-inflammatory, immunomodulatory and catabolic activities. Therefore, aberrant expression of TNF-alpha could be important in the pathogenesis of MHC-associated immune disorders. A TNF-alpha variant with a polymorphism in its promoter region has been described and designated TNF2. TNF2 has been associated with a variety of MHC-linked diseases, including systemic lupus erythematosus, dermatitis herpetiformis and insulin-dependent diabetes mellitus (IDDM), as well as parasitic infections. TNF2 has previously been shown to be associated with the MHC haplotype HLA A1-B8-DR3-DQ2, which confers susceptibility to CD. We have analyzed the distribution of TNF2 alleles in a group of celiac patients (n = 52) compared to controls (n = 52) in an effort to evaluate its role, if any, in susceptibility to the condition. TNF2 has a frequency of 0.5000 (SE +/- 0.0490) in CD, compared to 0.1635 (+/- 0.0362) in a control sample (p < 10(-6)). Of 52 patients, 44 carried one or more TNF2 alleles. Analysis indicates that the distribution of TNF2 is best explained by assuming 100% allelic association between it and HLA-DQB1*0201 (frequency = 0.7791 +/- 0.0447). However, the number of TNF2 heterozygotes significantly exceeds expectations and measurements of linkage disequilibrium confirm that allelic associations spanning the DQ and TNF regions are strongly maintained in CD. Taken together, these results indicate that TNF2 may have a role in the pathogenesis of CD; however, since it is not an independent association, the possibility that TNF2 constitutes a passive component of the CD haplotype cannot be excluded.
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PMID:TNF2, a polymorphism of the tumour necrosis-alpha gene promoter, is a component of the celiac disease major histocompatibility complex haplotype. 881 55

To identify the binding motifs of peptides which bind to the celiac disease and insulin-dependent-diabetes-mellitus (IDDM)-associated DQ2 molecule, peptides were eluted from affinity-purified DQ2 molecules. The eluted peptides were separated by reverse-phase HPLC. Prominent peptide peaks and the remaining pool of peptides were sequenced by Edman degradation. Truncated variants of eight different peptides with a length of 9-19 amino acids were identified; among them class II-associated invariant chain peptides (CLIP) and peptides that stem from HLA class I alpha, HLA-DQ alpha 1*0501, Ig and CD20 molecules. Data from the pool sequencing and the biochemical binding analyses of synthetic variants of an eluted high-affinity ligand (HLA class I alpha 46-60), indicate that the side chains of amino acid residues at relative position P1 (bulky hydrophobic), P4 (negatively charged or aliphatic), P6 (Pro or negatively charged), P7 (negatively charged) and P9 (bulky hydrophobic) are important for binding of peptides to DQ2. Computer modeling of the DQ2 with variants of the high-affinity ligand in the groove suggests that peptides bind to DQ2 through the primary anchors P1, P7 and P9 and making additional advantageous interactions using the P4 and P6 positions.
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PMID:The peptide binding motif of the disease associated HLA-DQ (alpha 1* 0501, beta 1* 0201) molecule. 892 67


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