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)

The IIM are a heterogeneous group of systemic rheumatic diseases which share the common features of chronic muscle weakness and mononuclear cell infiltrates in muscle. A number of classification schemes have been proposed for them, but none takes into consideration the marked immunologic, clinical, and genetic heterogeneity of the various clinical groups. We compared the usefulness of myositis-specific autoantibodies (anti-aminoacyl-tRNA synthetases, anti-SRP, anti-Mi-2 and anti-MAS) to the standard clinical categories (polymyositis, dermatomyositis, overlap myositis, cancer-associated myositis, and inclusion body myositis) in predicting clinical signs and symptoms, HLA types, and prognosis in 212 adult IIM patients. Although patients with inclusion body myositis (n = 26) differed in having significantly more asymmetric and distal weakness, falling, and atrophy than other patients, there were few other significant differences among the other clinical groups. In contrast, autoantibody status defined distinct sets of patients and each patient had only 1 myositis-specific autoantibody. Patients with anti-amino-acyl-tRNA synthetase autoantibodies (n = 47), compared to those without these antibodies, had significantly more frequent arthritis, fever, interstitial lung disease, and "mechanic's hands"; HLA-DRw52; higher mean prednisone dose at survey, higher proportion of patients receiving cytotoxic drugs, and higher death rates. Those with anti-signal recognition particle antibodies (n = 7) had increased palpitations; myalgias; DR5, DRw52; severe, refractory disease; and higher death rates. Patients with anti-Mi-2 antibodies (n = 10) had increased "V-sign" and "shawl-sign" rashes, and cuticular overgrowth; DR7 and DRw53; and a good response to therapy. The 2 patients with anti-MAS antibodies were the only ones with alcoholic rhabdomyolysis preceding myositis; both had insulin-dependent diabetes mellitus, and both had HLA-B60, -C3, -DR4, and -DRw53. These findings suggest that myositis-specific autoantibody status is a more useful guide than clinical group in assessing patients with myositis, and that specific associations of immunogenetics, immune responses, and clinical manifestations occur in IIM. Thus the myositis-specific autoantibodies aid in interpreting the diverse symptoms and signs of myositis patients and in predicting their clinical course and prognosis. We propose, therefore, that an adjunct classification of the IIM, based on the myositis-specific autoantibody status, be incorporated into future studies of their epidemiology, etiology, and therapy.
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PMID:A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups. 165 47

In this study HLA-DQA1 and TNF genes in addition to HLA-DQB1 gene were investigated at DNA level for elucidation of the genetic backgrounds of Type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. DNA, amplified by polymerase chain reaction, was subjected to allele specific oligonucleotide dot blot analysis, restriction fragment length polymorphism analysis or DNA sequencing. Polymorphism of the TNF gene to NcoI did not correlate with Type 1 diabetes in Japanese patients. DQw1.2 had a protective effect against the disease, the DQA1*1 allele was significantly decreased and DQA1*3 allele was significantly increased. Seventeen out of twenty-two Type 1 diabetic patients (77%) were homozygous for DQA1*3 and five out of twenty-two (23%) heterozygous. The DQA1*3 gene of Type 1 diabetic patients had a normal nucleotide sequence. Furthermore, DQA1*3 was found unexpectedly in two patients without DR4 or DR9. These data indicate that DQA1 gene confers susceptibility and resistance to Type 1 diabetes in Japanese subjects.
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PMID:HLA-DQA1*1 contributes to resistance and A1*3 confers susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. 167 85

DQA1, DQA2, DQB1, and DRB1 alleles have been determined and the DQA1 and DQB1 DNA gene sequences assigned by using restriction fragment length polymorphisms in 67 diabetic individuals and 72 controls. It has been found that: 1) DQA2 (U allele) is not a susceptibility factor, 2) non-aspartic acid homozygosity in residue 57 (Asp 57 negative) of the DQ beta chains is positively correlated with insulin-dependent diabetes mellitus (IDDM), and 3) DQ beta Asp-57-negative and DQ alpha arginine-52-positive (Arg-52-positive) individuals are increased among diabetic patients; this latter analysis shows a higher etiologic fraction (delta) value than the one obtained when considering only homozygous DQ beta Asp-57-negative individuals. However, if only non-DR3 or DR4 individuals were considered (both in DQ beta Asp-57-negative homozygous and in DQ beta Asp-57-negative/DQ alpha Arg-52-positive individuals) the correlation with disease disappears. In addition, the postulated risk DQ beta Asp 57-negative and DQ alpha Arg 52 positive is absent in six patients. These data do not discard the possibility that DR3/DR4 may contain the primary susceptibility factors. It is concluded that it is not possible to assign the susceptibility to IDDM to a specific HLA locus and that several loci within the same or the trans haplotype may be involved.
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PMID:Exclusive HLA-DQ factors do not explain susceptibility to insulin-dependent diabetes. 167 4

The molecular basis of eight DR4 subtypes resides in several nucleotide substitutions in the third hypervariable region of the DR beta 1 chain. The typing of DR4 subsets using the mixed lymphocyte culture (MLC) assay or allele-specific oligonucleotide hybridization is expensive, cumbersome, and requires the use of radioisotopes. We have therefore developed a rapid and safe procedure for subtyping DR4-alleles that involves selective amplification of the second exon of the DR4-DRBI gene followed by unambiguous subtype discrimination after digestion with five allele-specific endonucleases [polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP)] and visualization of the polymorphic fragments with silver or ethidium bromide staining. Validity of this subtyping procedure was initially examined by the use of cell lines of known subtypes. Three groups of DR4 patients with insulin-dependent diabetes mellitus (IDDM) from Chinese, Tunisian, and Caucasian populations were subtyped and the prevalence of subtype associations with IDDM was compared.
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PMID:A simple nonradioactive method of DNA typing for subsets of HLA-DR4: prevalence data on HLA-DR4 subsets in three diabetic population groups. 168 Aug 38

The combination of the HLA complement allotypes BFS, C2C, C4AQ0 (deleted gene) and C4B1, termed SC01 complotype, usually present in the HLA-B8,DR3,DQw2 diabetogenic haplotype, has also been found in a novel "low frequency" HLA-B49,DR4,DQw8 haplotype associated with Spanish insulin-dependent diabetes mellitus (IDDM). Family studies of C4 antigenic determinants Rodgers/Chido and their specific C4d nucleotide sequences confirm that this novel haplotype bearing Chido -3, -6 is not due to a recent recombination from the common HLA-B8,DR3 haplotype bearing Chido 3,6; moreover, Chido analysis at the serological or DNA level is presently the only way to distinguish both SC01 complotypes, since BF, C2, steroid 21-hydroxylase and C4 genes do not reveal other differences by restriction fragment analysis. On the other hand, HLA-B49,SC01,DR4 is the first DR4-bearing IDDM-susceptible haplotype with a deleted C4 gene described so far and the only DR4-bearing haplotype found in the Spanish population. This report further supports the fact that extended haplotypes with deleted (or "not duplicated") genes in the class III region contain IDDM-susceptibility more often than non-deleted (or "duplicated") haplotypes in the Spanish and other Mediterranean populations.
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PMID:C4 Chido 3 and 6 distinguish two diabetogenic haplotypes: HLA-B49, SC01,DR4,DQw8 and B8,SC01,DR3,DQw2. 168 41

In this study we report for the first time, the molecular analysis of HLA-DR and -DQ gene frequencies in a large cohort of well characterized type 1 (insulin-dependent) diabetes mellitus (IDDM) patients (n = 72), and ethnically matched controls (n = 59) collected in sub-Saharan Africa. High molecular mass DNA was prepared and analyzed in Southern blots with DRB1, DQA1, and DQB1 probes. By identifying DR and DQ allele-specific restriction fragment length polymorphisms (RFLPs), we have shown a strong positive association between IDDM and the Asp 57- DQB1 allele *0201 (DQw2). A rare DR4, DQw2 haplotype was also identified at high frequency in the IDDM cohort. We can now confirm that the association between Asp 57-DQB1 alleles and IDDM, previously reported in ethnically diverse cohorts collected in Western Europe, North America, and South Asia, is also present in an IDDM cohort collected in Africa.
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PMID:Analysis of HLA-DR and -DQ gene polymorphisms in Sudanese patients with type 1 (insulin-dependent) diabetes. 168 74

Eighteen unrelated Chinese patients with insulin-dependent diabetes mellitus (IDDM) were analyzed for HLA Class II genes using a variety of molecular biological techniques including restriction fragment length polymorphism (RFLP), polymerase chain reaction with allele-specific oligonucleotides (PCR-ASO) and direct DNA sequencing. The high frequency of DR3/DR4 heterozygotes found in the Chinese with IDDM strengthens the importance of this combination of haplotypes in IDDM susceptibility since it is present in two genetically distant populations--Chinese and Caucasians. The frequency of DRw9, a rare allele in the Caucasian population, is much higher in the Chinese. Moreover, the DQ beta chain linkage of DRw9 was different in IDDM patients compared with control subjects. In contrast with previous results, codon 57 of the DQ beta chain was aspartic acid in DRw9 Chinese IDDM patients. Furthermore, one particular DRw9-DQw9 haplotype may be associated with IDDM susceptibility in the Chinese population.
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PMID:Aspartic acid at position 57 of the HLA-DQ beta chain in insulin-dependent diabetes mellitus: an association with one DRw9-DQw9 subtype in the Chinese population. 180 12

Eighty unrelated diabetic children, seventy healthy controls and hundred and ten affected and unaffected first-degree relatives of twenty multiplex families were investigated by restriction fragment length polymorphism analysis of HLA class II genes using five probe/enzyme systems: DRB and DQB/Taq I, DRB and DQB/EcoRI and DQB/BamHI according to standard procedures described in the 10th Histocompatibility Workshop protocol. Comparison between the unrelated diabetic patients and the controls confirmed the positive association of type 1 diabetes with DR3(w17)DQw2 Dw24 or Dw25 and DR4DQw8 and the negative association with DR2(w15)DQw6, DR4DQw7 and DR7DQw2 haplotypes. In multiplex families, similar allele associations were found and the distinction between haplotypes present in diabetic patients and those that segregated to healthy family members allowed to observe striking differences between the "affected" and "unaffected" haplotypes, particularly for the subtypes of DR3(w17) DQw2, DR4DQw3 and DR2DQw1 haplotypes. Heterozygous siblings who carried both DR3DQw2 and DR4DQw8 subtypes disclosed a highly increased risk and more than 80% of DR3/DR4 affected siblings received a paternal DR4DQw8 together with a maternal DR3DQw2. These observations indicate that several genetic aspects influence susceptibility to type 1 diabetes: 1) some particular HLA class II subsets; 2) the parental origin of the predisposing genes; 3) the synergistic effect of both haplotypes, in particular DR3DQw2 and DR4DQw8. These results may help to better specify susceptibility markers for risk prediction in siblings.
Diabetes Res 1991 Oct
PMID:DNA polymorphism analysis of HLA class II genes in unrelated children and in first-degree relatives with type I diabetes. 168 61

Interleukin 1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF-alpha) may be pathogenetically important in insulin-dependent diabetes mellitus (IDDM), which is associated with genes of the HLA region. Since a regulatory role of HLA region genes on monokine production may exist, we looked for an association between the monokine and prostaglandin E2 (PGE2) responses of monocytes (Mo) from 20 healthy males (18-50 years) with HLA-DR types relevant for IDDM susceptibility and resistance (DR1,2, DR1,3, DR1,4, DR3,4). Monokine assays were established and evaluated and the secretions of IL-1 beta, TNF-alpha, and PGE2 measured in Mo cultures (2h, 6h, 20h) prepared by endotoxin-free techniques and stimulated by low-dose E. coli lipopolysaccharides (LPS). There were no significant associations between Mo responses and HLA-DR phenotype. Likewise, Mo from DR2 (n = 5) and DR4 (n = 5) homozygous healthy males demonstrated no significant differences in monokine and PGE2 responses of Mo. In the HLA class III region a diallelic TNF-beta gene NcoI polymorphism consisting of alleles of 5.5 kb and 10.5 kb was recently described and associated with susceptibility to autoimmune diseases including IDDM. We report that IL-1 beta and TNF-alpha responses of Mo from TNF-beta 10.5 kb homozygous healthy individuals were significantly higher than for TNF-beta 5.5/10.5 kb heterozygotes. IL-1 beta and TNF-alpha responses of Mo from males (18-35 years) with newly diagnosed (n = 10) and long-standing IDDM (n = 10) and from age- and HLA-DR-matched healthy males (n = 10) were studied. LPS, gamma interferon (IFN), and TNF-alpha-stimulated Mo cultures were investigated. No significant differences were found between Mo responses of IDDM patients and controls. IFN (1000 U/ml) in the presence of LPS significantly potentiated LPS-stimulated Mo TNF-alpha secretion and reduced the levels of IL-1 beta immunoreactivity in Mo lysates. IFN and TNF-alpha did not have any effects on LPS-stimulated Mo secretion of IL-1 beta immunoreactivity. We conclude that Mo IL-1 beta and TNF-alpha production is normal in patients with recent-onset and long-standing IDDM. The interindividual differences in monokine responses may be accounted for by the diallelic human TNF-beta gene polymorphism rather than by HLA class II genes. This observation may be important for understanding the association of certain HLA haplotypes with autoimmune phenomena and disease.
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PMID:Monocyte function in IDDM patients and healthy individuals. 169 9

This article presents a model for the HLA effect in insulin-dependent diabetes mellitus (IDDM) that is almost the mirror image of a model suggested by Nepom. In the Nepom model, the products of certain HLA alleles are associated with IDDM because they bind and present a specific peptide or peptides so as to induce an immune response to pancreatic beta-cells; certain other alleles can protect against IDDM if they compete strongly for binding of the diabetogenic peptide. My model focuses instead on the failure of the immune system to maintain tolerance to pancreatic beta-cells. I suggest that the HLA alleles negatively associated with IDDM (e.g., DR2 and DQw1) produce products with high affinity for certain beta-cell peptide or peptides needed to establish and maintain tolerance to beta-cells, whereas the alleles that are common in IDDM (e.g., DR3, DR4, and DQw8) produce products that have low affinity for the tolerogenic peptide or peptides or that bind the peptide or peptides in the wrong orientation or configuration for establishing tolerance. I also discuss the multiplicity of HLA loci, alleles, and amino acids contributing to IDDM and the fact that the associations of specific loci, alleles, and even genotypes with IDDM depend not only on their intrinsic properties but also on various population parameters.
Diabetes 1992 Feb
PMID:HLA and insulin-dependent diabetes. A protective perspective. 173


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