Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

HLA class II molecules are surface glycoproteins which are essential in the initiation of immune responses. It has been postulated that induction of class II in epithelial cells such as endocrine cells, which are normally class II negative, may result in autoimmunity. In type I diabetes, islet beta cells, the target of the autoimmune process, selectively express class II antigens. But in contrast to most other cell types, islet beta cells are not stimulated to express class II by interferon-gamma (IFN-gamma) and thus the conditions under which this induction occurs have been particularly elusive. The cytotoxins tumour necrosis factor (TNF) and lymphotoxin (LT) synergize with IFN-gamma in a number of activities. We report here that IFN-gamma in combination with either TNF or LT induces islet cell class II expression. This finding has important implications for the pathogenesis of type I diabetes and the understanding of the differential control of class II expression.
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PMID:HLA class II induction in human islet cells by interferon-gamma plus tumour necrosis factor or lymphotoxin. 310 76

We have typed 27 Caucasoid families for DNA restriction fragment length polymorphisms and specific sequences using HLA class II specific cDNA, genomic and oligonucleotide probes. DNA haplotypes were identified by restriction fragment length polymorphism analysis that correlated with previously serologically-defined extended major histocompatibility haplotypes. These DNA haplotypes sort into positive, neutral or negative associations with Type 1 (insulin-dependent) diabetes mellitus. The DNA susceptibility haplotypes are even more simply and specifically defined by oligonucleotide probes for sequences of DQA and DQB genes. Our oligonucleotide probes define variabilities in nucleotide sequences coding for amino acid residues 26, 37 and 38 in the DQ beta-chain. Probes defining DQA sequences are also important for defining susceptibility since certain DQA genes appear to modify DQB susceptibility by conferring resistance. Thus, major histocompatibility conferred susceptibility to diabetes cannot be adequately explained by an amino acid change at a single position in the DQ beta-chain. These probes allow the direct identification of major histocompatibility susceptibility genes in Type 1 diabetes without the necessity of determining full haplotypes.
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PMID:Oligonucleotide probes for HLA-DQA and DQB genes define susceptibility to type 1 (insulin-dependent) diabetes mellitus. 324 Aug 36

Over half of the inherited predisposition to insulin-dependent diabetes mellitus maps to the region of chromosome 6 that contains the highly polymorphic HLA class II genes which determine immune responsiveness. Analysis of DNA sequences from diabetics indicates that alleles of HLA-DQ beta determine both disease susceptibility and resistance, and that the structure of the DQ molecule, in particular residue 57 of the beta-chain, specifies the autoimmune response against the insulin-producing islet cells.
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PMID:HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. 330 80

To examine the nature of HLA-linked genetic susceptibility to insulin-dependent diabetes mellitus (IDDM), we compared HLA class II gene sequences from IDDM patients and control individuals. Genomic libraries were constructed from two siblings with IDDM, typed serologically as DR3,w6 and DR3,4. These libraries represent the HLA haplotypes (DR3, DR4) most frequently associated with IDDM, as well as one haplotype found less often. Individual genomic clones were identified and assigned to specific loci and haplotypes. The nucleotide sequence was then determined from the variable second exon from the HLA-DQ alpha, DQ beta, and DR beta genes from all three haplotypes. Sequence variation within the DQ alpha genes could not be correlated with the disease. For all three haplotypes, the DQ alpha sequence from the IDDM patient was identical to the DR-matched control sequence. Similarly, for the DR3 haplotype, the DQ beta sequences matched all control DR3 alleles. The DQ beta sequence from the DR4 haplotype was identical to the predominant DR4 allele (DQ beta 3.2) but differed at four amino acid residues from the other major DR4 DQ beta sequence (DQ beta 3.1) found rarely among IDDM patients. Sequence analysis of the DQ beta gene from the DRw6 haplotype revealed a new allele that differed from the DQ beta allele from a control DR6 allele at two residues. The DR beta genes from these three haplotypes also did not show any sequence features uniquely associated with IDDM, although the frequency of certain allelic variants in all three of these haplotypes may be altered in the IDDM population. A particular group of amino acids was found to be shared between the DR beta-1 alleles from the DR4 and DRw6 haplotypes and may be involved in genetic susceptibility to IDDM.
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PMID:Sequence analysis of HLA class II genes from insulin-dependent diabetic individuals. 337 63

Genetic associations with Type 1 (insulin-dependent) diabetes may be primary or secondary to linkage disequilibrium. Studies of different racial groups should allow these to be distinguished. We have reported that Type 1 diabetes is associated with HLA-DR3 and -DR4 in subjects of North Indian (Punjab) origin and now present the results of a study of HLA class II DNA polymorphisms in this group and in white caucasoid subjects. DR4 in North Indian Type 1 diabetic patients was associated with DQ beta and DX alpha DNA polymorphisms identical to those found in DR4-positive white caucasoid patients. This DQ beta/DX alpha pattern was increased in frequency in North Indian diabetic patients vs control subjects (33.3% vs 8.5%, p less than 0.001, relative risk = 5.12 (95% confidence limits: 1.96-13.4)). A DQ beta polymorphism with very low relative risk for Type 1 diabetes in white caucasoid subjects was also markedly reduced in North Indian diabetic patients vs control subjects (2.3% vs 24.7%, p less than 0.02, relative risk = 0.10 (95% confidence limits: 0.02-0.46)). This pattern was associated with DR2 in white caucasoid subjects, but with DRw6 in North Indians. A DR3-associated DR beta polymorphism was markedly increased in North Indian diabetic patients vs control subjects (90.2% vs 40.7%, p less than 10(-6), relative risk = 12.1 (95% confidence limits: 4.32-33.9)). The DQ subregion may be a primary site of genetic influence on susceptibility to Type 1 diabetes. Further studies in different racial groups will clarify the HLA associations of Type 1 diabetes.
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PMID:Class II HLA DNA polymorphisms in type 1 (insulin-dependent) diabetic patients of north Indian origin. 341 56

The HLA class II genes control immune responsiveness to defined antigens; they encode cell surface heterodimers composed of alpha and beta glycopeptides. Recently, cDNA and genomic clones encoding these chains have been isolated, which allows molecular analysis of the class II genes. cDNA clones encoding the alpha chain of the HLA-DR antigen as well as that of another HLA class II antigen have been identified and characterized by nucleotide sequence analysis. These clones have been used as probes to isolate additional class II alpha cDNA clones in cDNA libraries and to identify polymorphisms in genomic DNA. Polymorphic restriction sites have been localized within the HLA-DR alpha gene and used as genetic markers in the analysis of families and of disease (insulin-dependent diabetes mellitus) and control populations. In addition, cDNA clones encoding the DR beta and DC beta chains were used as hybridization probes to identify DNA polymorphism. cDNA clones encoding the DR gamma (Ii) chain have also been identified; unlike the DR alpha and DR beta loci, the DR gamma gene is located on some chromosome other than chromosome 6. The genetic complexity of the human class II alpha and beta loci, as revealed by analysis with cDNA and genomic clones, is greater than that of the murine class II genes. The extent of that complexity will be defined by future work in this area.
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PMID:Analysis by molecular cloning of the human class II genes. 609 60

Non-insulin-dependent diabetes mellitus has been recognized to be heterogeneous in etiology, with multiple subgroups. Several genes or chromosomal regions have been implicated in the development of the disease. In this study the association of HLA class II alleles and genotypes and the association of CD4 and CD3 polymorphisms were assessed in a large number of Belgian non-insulin-dependent diabetes mellitus patients. Furthermore, the importance of the DQ alpha 1Arg52/DQ alpha 1Arg52 and the DQ beta 1Asp57/DQ beta 1Asp57 genotypes and the combination of both genotypes were examined. Our results show that in the HLA class II genes only the DQ alpha 1Arg52+/DQ alpha 1Arg52+ genotype was significantly associated with non-insulin-dependent diabetes mellitus compared with controls (p = 0.011, RR = 2.02). We also observed that the frequency of the CD4*A4/*A8 genotype and the CD4*A7 allele was significantly increased and decreased respectively in non-insulin-dependent diabetes mellitus patients as compared with the controls (p = 0.018, RR = 2.16 and p = 0.0003, RR = 0.49 respectively). These results therefore suggest that HLA class II and CD4 genes might independently contribute to the susceptibility for non-insulin-dependent diabetes mellitus and that these alleles and genotypes might identify subgroups of patients with different susceptibilities.
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PMID:Increased and decreased relative risk for non-insulin-dependent diabetes mellitus conferred by HLA class II and by CD4 alleles. 755 46

It is known that certain combinations of alleles within the Human Leukocyte Antigen (HLA) Complex are associated with susceptibility or resistance to insulin-dependent diabetes mellitus (IDDM). The association of DR and DQ with IDDM has been well documented. Even though the association of specific DP alleles with some autoimmune diseases (i.e. juvenile rheumatoid arthritis [JRA] and celiac disease) has already been demonstrated, the role of HLA-DP genes in IDDM remains uncertain. A previous study conducted on a group of diabetic Venezuelan families with IDDM proband demonstrated that the HLA-DRB1*04-DQA1*03-DQB1*0302 and DRB1*03-DQA1*0501-DQB1*0201 combinations present a strong association with susceptibility to IDDM. The availability of this population enabled us to assess further susceptibility associated with other HLA class II alleles. We analysed HLA-DPA1 and DPB1 genes of 42 Venezuelan families with one IDDM proband and of 32 healthy families by oligotyping (PCR-SSO) using primers and probes from the XIth Histocompatibility Workshop. In contrast with previous data reported in other populations, the HLA DPA1*01-DPB1*0202 was the only haplotype significantly associated with IDDM in the Venezuelan population studied. In most cases the data showed this HLA DP allele combination as a part of the HLA DRB1*03-DQA1*0501-DQB1*0201 haplotype positively associated with IDDM, indicating a linkage disequilibrium between the alleles involved in this HLA DR-DQ-DP haplotype and as a consequence, a secondary role of HLA-DP genes in conferring susceptibility to the development of the disease. The analysis also indicates a non-significant increase of HLA DPA1*01-DPB1*0301 and DPA1*02-DPB1*1301 haplotypes among diabetics. However, both combinations were in 50% of the cases associated with the HLA DRB1*04-DQA1*03-DQB1*0302 haplotype. These data and their comparison with HLA DR-DQ-DP haplotypes in more homogeneous ethnic groups support the existence of a weak association of IDDM with specific HLA DP alleles and indicate how the distribution of these DP alleles could differ depending on the ethnic groups studied.
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PMID:HLA-DP and susceptibility to insulin-dependent diabetes mellitus in an ethnically mixed population. Associations with other HLA-alleles. 757 3

Genetic susceptibility to many autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM) is statistically linked to the HLA class II region of chromosome 6. However, a distinguishing feature of patients with HLA class II-linked autoimmune disease is an abnormally low density of conformationally correct, self-peptide filled HLA class I molecules on the lymphocyte cell surface. The transporters associated with antigen processing (Tap-1 and Tap-2) are essential for normal class I expression and presentation of intracellular peptides, and these genes are located within the HLA class II region. The aims of this project were to determine if Tap genes could be implicated in the defective class I expression associated with IDDM by using a novel Epstein-Barr virus (EBV)-mediated gene transfer system to introduce a cloned, normal Tap-2 or Tap-1 gene into B cell lines from normal and IDDM patients and analyzing the effect on conformationally dependent class I expression. The results show that Tap-2 gene transfer in B cells from 40% of randomly selected IDDM patients increased expression of conformationally correct, cell-surface class I molecules to levels comparable with similarly treated B cells from normal control individuals. B cells from another 40% of IDDM patients responded to Tap-1 gene transfer. These effects were specific because B cells from normal individuals did not respond to Tap-1 or Tap-2 gene transfer with increased class I expression, and B cells from IDDM patients responding to Tap-2 gene transfer did not respond to Tap-1 gene transfer and vice versa. Thus, these complementation studies identify distinct, non-overlapping subsets of IDDM patients whose class I defect in B cells can be reversed by Tap-1 or Tap-2 gene transfer. The increase in class I expression induced by Tap gene transfer is associated with a reduction in the number of peptide-empty class I molecules as demonstrated by the response to exogenous peptide loading. Furthermore, the increase in self-peptide filled class I molecules induced by Tap gene transfer into B cells from IDDM patients is associated with restored antigen presentation to autologous T cells. These studies conclude that Tap gene dysfunctions may contribute to the defect in class I phenotype and antigen presentation demonstrated by IDDM patients. Defective presentation of self-peptides by antigen presenting cells can lead to the failed T cell education and tolerance to self antigens evident in IDDM. These studies functionally identify HLA class II region genes that contribute to an immunologic defect in IDDM.
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PMID:Tap-1 and Tap-2 gene therapy selectively restores conformationally dependent HLA Class I expression in type I diabetic cells. 757 13

The TAP2 gene, located in the HLA class II region, encodes a subunit of a transporter involved in the endogenous antigen-processing pathway, and has been suggested to contribute to the genetic risk for insulin-dependent diabetes (IDDM). In order to determine whether the TAP2 locus modulates the risk conferred by HLA DQ loci, HLA DQA1-DQB1-TAP2 haplotypes were analysed in 48 IDDM probands, their first degree relatives, and in 62 normal control subjects. A decreased frequency of the TAP2B allele was confirmed in this IDDM cohort (12 vs 28% in control subjects, pc < 0.05). Analysis of 73 informative meiotic events in IDDM and control families demonstrated a recombination fraction between HLA DQB1 and TAP2 loci of 0.041 (Log of the odds score = 16.5; p < 10(-8)) indicating strong linkage between these loci. Family haplotype analysis demonstrated linkage disequilibrium between TAP2 and HLA DQA1-DQB1, and showed that the reduced frequency of TAP2B was associated with its absence on the IDDM susceptible DQA1*0301-DQB1*0302 haplotype, its low frequency on DQA1*0501-DQB1*0201, and the association of TAP2B with DQA1*0101-DQB1*0501 haplotypes which were less frequent in IDDM patients. Comparison of transmitted with non-transmitted haplotypes in IDDM families showed a slight but not significant decrease in TAP2B allele frequency on transmitted (3 of 37) vs non-transmitted (2 of 9) HLA DQA1*0501-DQB1*0201 haplotypes. No other differences were observed. Twenty-four unrelated DQA1*0501-DQB1*0201 haplotypes from non-diabetic families had a TAP2B allele frequency (4%) similar to that in IDDM haplotypes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HLA DQA1-DQB1-TAP2 haplotypes in IDDM families: no evidence for an additional contribution to disease risk by the TAP2 locus. 758 84


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