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)

Apart from genes in the HLA complex (IDDM1) and the variable number of tandem repeats in the 5' region of the insulin gene (INS VNTR, IDDM2), several other loci have been proposed to contribute to IDDM susceptibility. Recently, linkage and association have been shown between the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene on chromosome 2q and IDDM. In a registry-based group of 525 recent-onset IDDM patients <40 years old we investigated the possible interactions of a CTLA-4 gene A-to-G transition polymorphism with age at clinical disease onset and with the presence or absence of established genetic (HLA-DQ, INS VNTR) and immune disease markers (autoantibodies against islet cell cytoplasm (ICA); insulin (IAA); glutamate decarboxylase (GAD65-Ab); IA-2 protein tyrosine phosphatase (IA-2-Ab)) determined within the first week of insulin treatment. In new-onset IDDM patients. G-allele-containing CTLA-4 genotypes (relative risk (RR)= 1.5; 95% confidence interval (CI) = 1.2-2.0; P < 0.005) were not preferentially associated with age at clinical presentation or with the presence of other genetic (HLA-DR3 or DR4 alleles; HLA-DQA1*0301-DQB1*0302 and/or DQA1*0501-DQB1*0201 risk haplotypes; INS VNTR I/I risk genotype) or immune (ICA, IAA, IA-2-Ab, GAD65-Ab) markers of diabetes. For 151 patients, thyrogastric autoantibodies (anti-thyroid peroxidase, anti-thyroid-stimulating hormone (TSH) receptor, anti-parietal cell, anti-intrinsic factor) were determined, but association between CTLA-4 risk genotypes and markers of polyendocrine autoimmunity could not be demonstrated before or after stratification for HLA- or INS-linked risk. In conclusion, the presence of a G-containing CTLA-4 genotype confers a moderate but significant RR for IDDM that is independent of age and genetic or immune disease markers.
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PMID:CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers. The Belgian Diabetes Registry. 935 55

The genes encoding the HLA-DQ heterodimer molecules, DQB1 and DQA1, have been found to have the strongest association with IDDM risk, although there is cumulative evidence for the effect of other gene loci within the major histocompatibility complex gene region. After the HLA-DQ locus, the HLA-DR locus has been suggested most often as contributing to the disease susceptibility. In this study we analyzed at the population level the effect of DR4 subtypes and class I, HLA-B alleles, on IDDM risk when the influence of the DQ locus was stratified. In all three populations studied (Estonian, Latvian, and Russian), DQB1*0302 haplotypes most frequently carried DRB1*0401 or DRB1*0404. DRB1*0401 was the most prevalent subtype in IDDM patients, whereas DRB1*0404 was decreased in frequency. DRB1*0402 was also prevalent among Russian haplotypes, but was not associated with IDDM risk. When HLA-B alleles were analyzed, strong associations between the presence of specific B alleles and DRB1*04 subtypes were detected. The HLA-B39 allele was found significantly more often in DRB1*0404-DQB1*0302-positive patients than in healthy control subjects positive for this haplotype: 27 of 54 (50%) vs. 4 of 49 (8.2%) (P < 0.0001). The results demonstrate that DQ and DR genes cannot explain all of the HLA-linked susceptibility to IDDM, and that the existence of a susceptibility locus telomeric to DR is probable.
Diabetes 1997 Nov
PMID:The effect of HLA-B allele on the IDDM risk defined by DRB1*04 subtypes and DQB1*0302. 935 41

The impact of matching for the human leukocyte antigen (HLA)-DQ phenotype in cadaveric renal transplantation is unclear. We analyzed the effect of matching serologically defined HLA-DQ phenotypes on renal allograft survival in 12,050 first cadaveric renal transplants (recipients were 63.5% white and 36.5% African-American). Recipients were entered into the South-Eastern Organ Procurement Foundation (SEOPF) database between 1 October 1987 and 6 June 1995. A series of life table analyses were done to test the equality of survival curves for HLA-DQ match, both alone and accommodating for differences in recipient race and HLA-DR match. Cox regression models were then performed to detect differences in allograft survival based upon HLA-DQ match. Initial adjustments were done by recipient race. Subsequent adjustments were done by recipient and donor race, age and sex, cold ischemia time (CIT), body mass index (BMI), cyclosporine A (CyA) use, peak panel reactive antibody (PRA) titer, year of transplant, presence of diabetes mellitus (DM), and degree of HLA-A,B and HLA-DR match as covariates. The effect of varying degrees of HLA-DQ match on graft survival were similar between the two races (p = 0.87). In all recipients, an 8.3% reduction in graft failure was observed for each increase in HLA-DQ match using the Cox regression model adjusted only for recipient race (p = 0.004). A non-significant 3.0% reduction in graft failure (p = 0.38) was observed for each level of increasing HLA-DQ match when using the Cox regression model adjusted for recipient and donor race, age and sex, CIT, BMI, CyA use, year of transplant, DM, HLA-A,B and -DR match. In this model, superior HLA-A,B match and HLA-DR match, recipient and donor age, male donor sex, shorter CIT, white race of recipient, lower peak PRA, CyA use, and absence of DM significantly improved graft survival (all < or = 0.004). We conclude that HLA-DQ matching does not significantly affect cadaveric renal allograft survival once adjusted for other known predictors of graft outcome.
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PMID:HLA-DQ matching in cadaveric renal transplantation. 936 45

Only weak associations have been found for particular environmental factors and development of insulin-dependent diabetes mellitus (IDDM). Very few studies have, however, accounted for genetic susceptibility when cases and controls have been compared. The genetics of IDDM is complex, but the HLA-DQ genes are the most important. There are many different combinations of DQA1 and DQB1 genes conferring disease risk to differing degrees. The strategy of NOBADIA (Norwegian Babies against Diabetes) is to identify at birth the babies in the general population with the highest genetic risk for developing IDDM: those carrying DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 (for simplification, hereafter named DQ2/DQ8). Four per cent of Norwegian babies carry this genotype which accounts for 46% of future cases of IDDM. Babies carrying the IDDM high-risk genotype have a lifetime risk of 12% for developing the disease. This is very close to the risk of a first-degree relative with the same genotype. DQ2/DQ8 heterozygotes also acquire the disease earlier than those with a lower genetic risk. Parents of children carrying the DQ2/DQ8 genotype will be informed and offered regular follow-up with blood samples and questionnaires at their public health care centre.
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PMID:Genetics in the prediction of insulin-dependent diabetes mellitus: from theory to practice. 945 85

The WHO DiaMond Molecular IDDM Epidemiology Sub-Project is testing the hypothesis that population variation in the frequency of high-risk HLA-DQ alleles is a primary determinant of the global patterns of IDDM incidence. Data are currently available for 16 populations, and reveal significant variations in the frequencies of HLA-DQA1 and DQB1 alleles among the case and the control groups. However, DQA1 x Arg-(52) and DQB1 x non-Asp-57 (ND) were consistent and independent markers of IDDM susceptibility in all populations, except Japan. Individuals who carried only DQA1 x R and DQB1 x ND alleles had an IDDM risk similar to that observed for first degree relatives of affected individuals (3%-5%). Such information is essential for the development of clinical strategies or disease prevention approaches for the general population or individuals at high-risk. Thus, the DiaMond Molecular Epidemiology Sub-Project provides an excellent model that can be followed to assess the impact of new genetic discoveries on medicine and public health practice for diabetes and other chronic diseases.
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PMID:Molecular epidemiology of insulin-dependent diabetes mellitus: WHO DiaMond Project. WHO DiaMond Molecular Epidemiology Sub-Project Group. 950 18

We analyzed 11 markers in the IDDM1 region in 120 IDDM patients and 83 healthy control subjects who were fully matched for the highest risk HLA-DQA1*0301-DQB1 *0302/DQA1*0501-DQB1*0201 genotype. Our study provides strong evidence that two regions in the major histocompatibility complex contribute to IDDM susceptibility or protection. First, despite selection for highest IDDM-associated risk DQ genotypes, this region displays extensive linkage disequilibrium (LD) differences between IDDM patients and control subjects. A second critical region was mapped around the microsatellite locus D6S273 centromeric of TNF, and it is approximately 200 kb in size. LD analysis shows that "diabetogenic haplotypes" may have resulted from a recombination telomeric of D6S1014 in the region of D6S273 and TNFa. Haplotype analysis using HLA and microsatellite loci refines IDDM risk assessment in carriers of the HLA-DQ highest risk genotype.
Diabetes 1998 Feb
PMID:Genetic structure of IDDM1: two separate regions in the major histocompatibility complex contribute to susceptibility or protection. Belgian Diabetes Registry. 951 23

The study of peptide binding to HLA class II molecules has mostly concentrated on DR molecules. Since many autoimmune diseases show a primary association to particular DQ molecules rather than DR molecules, it is also important to study the peptide-binding properties of DQ molecules. Here we report a biochemical peptide-binding assay for the type I diabetes-associated DQ8, i.e. DQ (alpha1*0301, beta1*0302), molecule. Affinity-purified DQ8 molecules were tested in peptide-binding assays using a radiolabelled influenza haemagglutinin (Ha) peptide encompassing positions 255-271(Y) as an indicator peptide. The Ha 255-271(Y) peptide bound to DQ8 in a pH-dependent fashion showing optimal binding around pH 5. The association kinetics were relatively slow and the resulting complexes were heat labile. The specificity of peptide binding to DQ8 was investigated in competitive inhibition experiments with a panel of 43 peptides of different lengths and sequences. The DQ8 molecules showed a different pattern of peptide binding compared to a previously studied DQ2 molecule. Peptides derived from thyroid peroxidase, HLA-DQ(alpha1*0301), HLA-DQ(alpha1*0302), retinol receptor and p21ras were among the high-affinity binders, whereas peptides derived from myelin basic protein were among the low-affinity binders. The sequence of the high-affinity peptides conformed with a previously published peptide-binding motif of DQ8.
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PMID:A peptide-binding assay for the disease-associated HLA-DQ8 molecule. 965 24

Autoimmune diabetes is the clinical end point for a sequential cascade of immunologic events that occur in a genetically susceptible individual. Structural and functional analysis of the HLA class II susceptibility genes in IDDM suggests likely molecular mechanisms for several of the key steps in this cascade of autoimmune events. We outline a pathway in which the HLA-DQ genes associated with IDDM bias the immunologic repertoire toward autoimmune specificities, creating an autoimmune-prone individual, followed by amplification and triggering events that promote subsequent immune activation. There are several direct links between genetics and autoimmune disease in this pathway: the developmental maturation of T-cells in a genetically susceptible individual occurs through molecular interactions between the T-cell receptor and the HLA-peptide complex. Selection of T-cells with receptors likely to contribute to autoreactivity may preferentially occur in the context of specific HLA-DQ alleles that are diabetes prone, because of inefficiencies in the peptide-MHC structural interactions of these molecules. Subsequent activation of these T-cells in the context of recognizing islet-associated antigens can trigger a poorly regulated immune response that results in progressive islet destruction. These subsequent diabetes-specific events are also directed by specific HLA genes, most prominently by the binding of specific antigenic peptides by the disease-associated HLA molecules. In this sequential cascade, opportunities for environmental influences and modulation by non-HLA genes are identified that likely act in concert with the predominant genetic susceptibility contributed by the HLA molecules themselves. Clarification of the steps in this pathway extends our understanding of the prevailing role of HLA genes in IDDM pathogenesis and suggests opportunities to intervene at discrete initiating, disease-promoting, or regulatory steps in IDDM development.
Diabetes 1998 Aug
PMID:Molecular basis for HLA-DQ associations with IDDM. 970 14

HLA-DQ alleles are closely associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM) but the immunologic mechanisms involved are not understood. Structural studies of the IDDM-susceptible allele, HLA-DQA1*0301/DQB1*0302, have classified it as a relatively unstable dimer, particularly at neutral pH. This is reminiscent of studies in the nonobese diabetic mouse, in which I-A(g7) is relatively unstable, in contrast to other murine I-A alleles, suggesting a correlation between unstable MHC class II molecules and IDDM susceptibility. We have addressed this question by analysis of dimer stability patterns among various HLA-DQ molecules. In EBV-transformed B-lymphoblastoid cell lines and PBL, the protein encoded by the IDDM-protective allele HLA-DQA1*0102/DQB1*0602 was the most SDS stable when compared with other HLA-DQ molecules, including HLA-DQA1*0102/DQB1*0604, a closely related allele that is not associated with protection from IDDM. Expression of six different HLA-DQ allelic proteins and three different HLA-DR allelic proteins in the bare lymphocyte syndrome cell line, BLS-1, revealed that HLA-DQA1*0102/DQB1*0602 is SDS stable even in the absence of HLA-DM, while other HLA class II molecules are not. These results suggest that the molecular property of HLA-DQ measured by resistance to denaturation of the alphabeta dimer in SDS may play a role in IDDM protection.
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PMID:Exceptional stability of the HLA-DQA1*0102/DQB1*0602 alpha beta protein dimer, the class II MHC molecule associated with protection from insulin-dependent diabetes mellitus. 983 37

Self peptides bound to HLA-DQ7 (alpha1*0501-beta1*0301), one of the HLA molecules associated with protection against insulin-dependent diabetes mellitus, were characterized after their acid elution from immunoaffinity-purified HLA-DQ7 (alpha1*0501-beta1*0301) molecules. The majority of these self peptides derived from membrane-associated proteins including HLA class I, class II, class II-associated invariant chain peptide and the transferrin-receptor (TfR). By in vitro binding assays, the specificity of these endogenous peptides for HLA-DQ7 (alpha1*0501-beta1*0301) molecules was confirmed. Among these peptides, the binding specificity of the TfR 215-230 self peptide was further examined on a variety of HLA-DQ and DR dimers. Several findings emerged from this analysis: (1) this peptide displayed HLA-DQ allelic specificity, binding only to HLA-DQ7 (alpha1*0501-beta1*0301); (2) when either the DQalpha or DQbeta chain was exchanged, little or no binding was observed, indicating that specificity of HLA-DQ peptide binding was determined by polymorphic residues of both the alpha and beta chains. (3) Unexpectedly, the TfR 215-230 self peptide, eluted from DQ, was promiscuous with regard to HLA-DR binding. This distinct DR and DQ binding pattern could reflect the structure of these two molecules as recently evidenced by crystallography.
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PMID:Naturally processed peptides from HLA-DQ7 (alpha1*0501-beta1*0301): influence of both alpha and beta chain polymorphism in the HLA-DQ peptide binding specificity. 984 27


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