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)

The human leukocyte antigen (HLA) class II genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 has been identified as a marker strongly predisposing to insulin-dependent diabetes mellitus (IDDM) in Caucasian populations. Its frequency in control populations (1-3%) is still, however, 1 order of magnitude higher than the prevalence of IDDM, suggesting that its penetrance can be modified by protective factors. In this study we searched for such a factor in the DRB1 locus by studying DRB1*04 polymorphism in 174 European Caucasian IDDM patients and 73 nondiabetic control subjects, all sharing the HLA-DR3/DR4 phenotype. Significant protection was encoded by the DRB1*0403 allele, which was observed in 5 of 49 control subjects (10%) and none of 171 IDDM patients (0%) with the DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype (RR = 0.02 [0.01-0.18], P < 0.0005). These data support the concept that protective HLA class II genes can overrule the risk caused by HLA-DQ susceptibility dimers. They also contribute to a possible strategy to screen for nondiabetic individuals with increased genetic risk of developing IDDM.
Diabetes 1995 May
PMID:DRB1*0403 protects against IDDM in Caucasians with the high-risk heterozygous DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype. Belgian Diabetes Registry. 772 10

The association between human leukocyte antigen (HLA) and insulin-dependent diabetes was studied in a large population-based investigation using genotyping of 425 new-onset patients, 0-14 years of age, and 367 matched control subjects. As many as 97% of patients compared with 75% of control subjects were positive for one or several of DQA1*0301, DQA1*0501, DQB1*0302, or DQB1*0201. Asp-57 DQB was present among 28% of patients, indicating that this residue alone does not confer protection. Combining Asp-57 DQB1 with either Arg-52 DQA1 or Leu-69 DQA1 did not explain susceptibility or protection either. DQA1*0301-DQB1*0302 (DQ8) and DQA1*0301-DQB1*0301 (DQ7) are identical except for four amino acid substitutions in the beta-chain, but DQ8 was positively (odds ratio 8.07; P < 0.001) and DQ7 negatively (odds ratio 0.38; P < 0.001) associated with the disease. Molecular modeling was used to determine whether physiochemical properties such as steric factors and surface electrostatic potentials also differ in a systematic way for various DQ molecules. Amino acids were substituted systematically at the four polymorphic sites, and the solvent-accessible surfaces and electrostatic potentials were computed for each molecule. Dramatic alterations in electrostatic potential were seen for double substitutions at position 45 (G45E) and 57 (A57D) of DQB1. The variation of physicochemical properties due to polymorphic substitutions may be significant to the mechanism of HLA-DQ association with insulin-dependent diabetes, via the effect these property variations have on peptide antigen binding selectivity and subsequent interactions with specific T-cell receptors.
Diabetes 1995 Jan
PMID:Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM. Members of the Swedish Childhood Diabetes Study. 781 6

Polymorphisms in HLA class II genes have been shown to contribute to susceptibility or protection against insulin-dependent diabetes mellitus (IDDM). In the present study the role of HLA class II haplotypes and the role of DQ alpha Arg52, DQ beta Asp57 and of polymorphic amino acids, located in the antigen-binding groove and the CD4-binding domain of the DR beta 1 chain, were studied in 210 unrelated Caucasian IDDM patients and 205 controls. The results showed that the genotype homozygous for DR beta 1Lys71+, which is in linkage disequilibrium with DQ alpha 1Arg52+ provided a major risk (relative risk, RR = 15.46) for IDDM and that combination of DR beta 1Lys71+/+ with homozygosity for DQ beta qAsp57-/- of the DQ beta 1 chain significantly increased the RR for developing IDDM (RR = 20.41). The DQ alpha 1Arg52(-)-DQ beta 1Asp57+ haplotype in cis or trans position conferred the highest protection against IDDM (RR = 0.08). Our findings confirm that protection against IDDM is provided by HLA-DQ loci but that susceptibility for IDDM is provided by both HLA-DRB1 and DQB1 loci. Our results also provide a new and more specific approach to determine the risk of any random Caucasian individual to develop IDDM. Indeed, increased susceptibility or protection against IDDM can be determined by the rapid and simple typing of DR beta 1Lys71, DQ alpha 1Arg52 and DQ beta 1Asp57 in a random person.
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PMID:Improved risk assessment for insulin-dependent diabetes mellitus by analysis of amino acids in HLA-DQ and DRB1 loci. 783 77

Genetic susceptibility to several autoimmune disorders is associated with the expression of certain MHC class II alleles. Insight into the etiology of such diseases awaits the identification of the class II restriction elements and the possible pathogenic peptides. Towards these aims, self-peptides bound to HLA-DQ1 and HLA-DQ8, allotypes considered to be neutral and permissive respectively towards the development of insulin-dependent diabetes mellitus, are reported. These naturally processed peptides were isolated from immunoaffinity purified HLA-DQ molecules expressed in cultured B lymphocytes. The chromatographic profiles of the peptide repertoires are unique, whereas the size distributions exhibit general similarity to those reported for naturally processed self-peptides bound to HLA-DR. Twenty-eight individual peptides representing 10 nested sets were identified by combined Edman microsequencing and mass spectrometry. Peptide length varied from 13 to 74 amino acids. Source proteins included MHC molecules and other integral membrane proteins, as well as secretory, cytosolic and mitochondrial proteins. Promiscuous invariant chain peptides were identified among the self-peptides bound to HLA-DQ8. No dominant amino acid markers suggestive of particular enzymatic processing events were detected. Some structural features of DQ1 and DQ8 that may relate to the bound peptides are discussed. Peptide specificity was confirmed in binding assays with purified HLA-DQ and HLA-DR protein.
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PMID:Self-peptides bound to the type I diabetes associated class II MHC molecules HLA-DQ1 and HLA-DQ8. 786 57

In the present study we characterized the frequencies of two polymorphisms within the MHC-linked heat shock protein (HSP) 70 genes in patients with insulin-dependent diabetes mellitus (IDDM) (n = 114) and healthy control individuals (n = 110). Significant differences in genotype and allelic frequencies were observed for both polymorphisms between randomly selected patients and controls. However, for the HSP70-2 polymorphisms this was solely due to linkage disequilibrium with DR3. The rate HSP70-Hom 2-allele was significantly more frequent in controls than in patients. It showed strong association with certain tumour necrosis factor (TNF) (class III) and HLA-B and -A (class I) alleles independent of HLA-DQ and -DR alleles. By typing 257 individuals from 55 IDDM multiple-case families two extended MHC-haplotypes, including class II-, TNF- and class I-markers, carrying the rare HSP70-Hom allele were defined. One was only transmitted to diabetic offspring, whereas the other was only transmitted to unaffected offspring. The functional implication of the polymorphism in the heat shock-inducible HSP70-2 gene was analysed by studying HSP70-2 mRNA expression after heat shock in peripheral blood mononuclear cells from individuals with different HSP70-2 genotypes. Preliminary data showed that individuals homozygous for the PstI 8.5-kb allele consistently had slightly lower expression than heterozygous and 9.0-kb homozygous individuals.
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PMID:Polymorphic analysis of the human MHC-linked heat shock protein 70 (HSP70-2) and HSP70-Hom genes in insulin-dependent diabetes mellitus (IDDM). 790 96

We established a T-cell line and 20 CD4+ T-cell clones from the peripheral blood lymphocytes of a type I diabetic patient using a membrane preparation of a rat insulinoma cell line (beta membrane antigen [BMA]) as a source of antigen. The T-cell line and three selected clones proliferated specifically to stimulation with BMA and to membranes prepared from human islets, rat pancreas, and NOD pancreas, but not to control antigens. Proliferation-inhibition studies using human leukocyte antigen (HLA)-specific monoclonal antibodies revealed HLA-DQw1-restricted recognition of BMA. An analysis of the T-cell receptor (TCR) repertoire of the T-cell line after 8 and 40 days of culture showed a prominent usage of the V alpha 1 and V alpha 12 gene families. Although sequencing of the TCR V alpha and V beta chains of the three clones demonstrated that each used different V alpha and V beta gene segments, structural similarities were found in complementary-determining region 3 (CDR3), the region that is postulated to interact with the peptide component of the TCR ligand. When we compared these TCR sequences with published sequences of disease-inducing T-cells of NOD mice, highly related TCR V beta families were detected. Furthermore, stretches of identical amino acids within the CDR3 region were found between two pairs of human and mouse T-cells. If one considers the species differences in TCR genes and sequence differences in the restriction elements for these cells (HLA-DQ vs. H-2 I-A nod), these sequence similarities are striking and may be useful for pinpointing T-cells of primary importance in the development of disease.
Diabetes 1994 Nov
PMID:HLA-DQ-restricted, islet-specific T-cell clones of a type I diabetic patient. T-cell receptor sequence similarities to insulitis-inducing T-cells of nonobese diabetic mice. 792 6

Transporter associated with antigen processing (TAP) is a molecule required for endogenous antigen processing and is encoded in MHC class II region. We have typed TAP polymorphism in 95 patients with insulin-dependent diabetes mellitus (IDDM) and 75 normal controls. TAP alleles were typed by PCR-SSO method. There was no significant difference between IDDM patients and normal controls in the frequencies of TAP 1 and TAP 2 alleles. On the contrary, HLA-DQ locus showed strong association with IDDM in the same series of subjects. Positive linkage disequilibrium was observed between HLA-DQB1*0303 and TAP 2C, and HLA-DQB1*0401 and TAP 2B. Negative linkage disequilibrium was observed between HLA-DQA1*0103 and TAP 2A. We conclude that it is not TAP but HLA-DQ that exhibits primary association with IDDM.
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PMID:[Analysis of TAP gene in IDDM]. 798 11

Previous studies have suggested an association between polymorphisms in the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Most of the studies so far have been performed in Caucasoid populations. We have investigated 418 random IDDM patients and 422 healthy control subjects from three different ethnic groups; Tanzanian blacks, Norwegian Caucasians and Japanese orientals. Our data suggest that polymorphisms in the insulin gene region confer susceptibility to IDDM in Caucasians, and that a similar tendency though not statistically significant is observed among Tanzanian blacks, while no significant contribution is seen among Japanese orientals. We further demonstrate that the disease-associated genotype INS +/+ confers susceptibility independently of HLA class II alleles associated with IDDM. Compared to the contribution of particular HLA-DQ alleles in IDDM susceptibility, the additional risk conferred by the insulin gene region polymorphism is, however, small. Genotyping of the insulin gene region will therefore most probably not be a useful tool in the prediction of IDDM.
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PMID:IDDM susceptibility associated with polymorphisms in the insulin gene region. A study of blacks, Caucasians and orientals. 798 75

TAP2 is a gene, located between HLA-DP and HLA-DQ, whose products form a transporter molecule involved in endogenous antigen processing. Polymorphic residues have been described in this gene. TAP2 is of particular interest because its involvement in antigen presentation makes it a candidate for a disease susceptibility gene. In psoriasis, two clinical subtypes analogous to the situation in diabetes type I with early onset and family history and type II with later onset and without family history have been described. We have previously shown that type I but not type II psoriasis is associated with the HLA-DRB1*0701/2, -DQA1*0201, -DQB1*0303 haplotype. To investigate whether this haplotype extends to include particular TAP2 and/or DP alleles, we tested the TAP2 and HLA-DP alleles of a control group (n = 199), patients with psoriasis type I (n = 66), and patients with psoriasis type II (n = 35) by hybridization with SSOs. Our data show that there is no significant correlation between TAP2 and/or HLA-DP gene polymorphism and psoriasis type I and/or type II. We conclude that disease association in type I psoriasis is associated with the extended haplotype HLA-B57, -Cw6, -DRB1*0701/2, -DQA1*0201, -DQB1*0303.
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PMID:Analysis of TAP2 and HLA-DP gene polymorphism in psoriasis. 800 77

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


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