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 HLA DR genotype frequencies in insulin-dependent diabetes mellitus (IDDM) patients and the frequencies of DR alleles transmitted from affected parent to affected child both indicate that the DR3-associated predisposition is more "recessive" and the DR4-associated predisposition more "dominant" in inheritance after allowing for the DR3/DR4 synergistic effect. B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. Heterogeneity is detected for both the DR3 and DR4 predisposing haplotypes based on DR genotypic class. With appropriate use of the family structure of the data a control population of "unaffected" alleles can be defined. Application of this method confirms the predisposing effect associated with the class 1 allele of the polymorphic region 5' to the insulin gene.
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PMID:HLA and insulin gene associations with IDDM. 256 57

In a prospective family study in Finland HLA genotyping was carried out for 1610 individuals from 422 consecutively registered families of children aged 14 years or younger with newly diagnosed insulin-dependent diabetes mellitus (IDDM). A haplotype (A2, Cw1, Bw56, w6, DR4) that has not been identified previously was the third most common (5.5%) among 746 haplotypes found in the probands. Only the haplotypes A1, Cw7, B8, w6, DR3 and A2, Cw3, Bw62, w6, DR4, which are well known to occur with high frequency in IDDM, were more frequent (10.7% and 9.7%, respectively). Among the 30 families in which a parent had IDDM, the newly identified haplotype was the most common haplotype transmitted from the diabetic parent to the proband (16.7%). Among 642 "non-diabetic" haplotypes (parental haplotypes not found in probands, or siblings or parents with IDDM), this haplotype was found only twice. This haplotype may partially explain the high incidence of IDDM in Finland.
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PMID:New susceptibility haplotype for type 1 diabetes. DIME Study Group. 256 4

The association of HLA class I and class II antigens, particularly HLA-B8,DR3, with a variety of autoimmune diseases has been well documented. The C4A*Q0 (non-expressed C4A) allele which is in linkage disequilibrium with HLA-B8,DR3 has also been reported to be associated with systemic lupus erythematosus, insulin-dependent diabetes mellitus and Graves' disease. However, the number of studies has been limited by the requirement of family data for the assignment of the C4A*Q0 allele based on C4 protein typing. Recently, with the availability of a C4 cDNA probe, a C4A gene deletion associated with HLA-B8,DR3 has been reported in normal individuals. We have tried to resolve the problem of assigning the C4A*Q0 allele by using both phenotypic and genotypic approaches and have determined the significance of the C4A*Q0 allele in 80 unrelated patients with Graves' disease and in 50 normal control subjects. Our results demonstrate a strong association of the C4A*Q0 allele with Graves' disease (56 versus 26%; P less than 0.002, relative risk = 3.7) and in particular in association with HLA-B8 and/or DR3 (92 versus 70.6%; P less than 0.04) when compared with normal controls. All the C4A*Q0 alleles that were associated with HLA-B8 and/or DR3 were due to a C4A gene deletion. Of the C4A*Q0 alleles, in Graves' disease, 94% (compared with 82% in the control group) could be detected by C4 DNA analysis using either TaqI or EcoRI restriction endonucleases. It is suggested that a combination of C4 protein typing with C4 DNA analysis is the best approach for the determination of the C4A*Q0 allele in unrelated individuals without access to family data.
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PMID:C4A gene deletion: association with Graves' disease. 257 May 94

Type 1 (insulin-dependent) diabetes mellitus, like some other autoimmune diseases, is linked to certain alleles coded by genes in the HLA-D region. Sequence analysis of DQ beta chains indicates that aspartic acid at codon 57 confers resistance to the development of Type 1 diabetes. However, a full explanation for the HLA-association of Type 1 diabetes, particularly the increased susceptibility of DR3/4 heterozygotes is still awaited. The localisation of tumour necrosis factor genes on the short arm of chromosome 6 between HLA-B and the complement genes (Class III) prompted us to investigate a possible polymorphism of TNF-alpha at the genomic level in relation to Type 1 diabetes susceptibility. A dialleleic TNF-alpha restriction fragment length polymorphism was found with Ncol and its segregation with HLA-haplotypes analysed in diabetic families. We describe here a strong linkage of TNF-alpha alleles with certain DR haplotypes. For example, the common extended haplotype HLA A1-B8-DR3 was almost exclusively associated with the 5.5 kb TNF-alpha allele whereas Bw62-DR4 with the 10.5 kb allele. Thus both alleles segregate to diabetic patients. DR matched haplotypes of affected family members differed significantly from those of the non-affected at the TNF alpha locus. All affected sibling pairs in 11 multiplex affected families were identical for TNF-alpha alleles, even if they were only haploidentical for HLA-B-DR haplotypes. In addition, heterozygosity for the TNF-alpha alleles was significantly more frequent in the patients. This tight linkage of TNF-alpha alleles with some extended haplotypes could help to explain the HLA-association of Type 1 diabetes as well as some other autoimmune diseases.
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PMID:TNF-alpha gene polymorphisms in type 1 (insulin-dependent) diabetes mellitus. 257 98

Class II restriction fragment length polymorphism studies of 38 pedigrees with multiple cases of insulin-dependent diabetes mellitus revealed the existence of a DQA1-related polymorphism that distinguishes two kinds of HLA-B8,DR3 haplotypes. One of these, characterized by the presence of DQA1-BglII 7.20 kb, was present in all 14 examples inherited by patients and in 6 of the 12 B8,DR3 haplotypes not so inherited. The apparently complete association between the presence of this fragment and the "affected" status of B8,DR3 haplotypes (p = 0.004) was confirmed in a separate group of 26 simplex pedigrees selected for the presence of this haplotype in the respective probands (combined p less than 0.0001).
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PMID:DQA1 restriction fragment length polymorphisms and insulin-dependent diabetes mellitus: a BglII fragment labels a subset of B8,DR3 haplotypes uniquely associated with insulin-dependent diabetes mellitus. 257 91

The localization of TNF genes on the short arm of chromosome 6 between HLA B and the complement genes focused attention to that genetic region which harbors many immunologically relevant genes and is also thought to hold susceptibility genes for a variety of autoimmune diseases that are linked to specific alleles of particular loci in the HLA D region. Since the recently established HLA-DR-DQ variation accounts only for part of the genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) we searched for genomic variation of the tumour necrosis factor (TNF) alpha. We have identified a TNF-alpha restriction fragment length polymorphism (RFLP) with NcoI and analysed diabetic patients including their families, controls and homozygous typing cell lines (HTC) defined by the 10th International Histocompatibility Workshop. Segregation analysis in families and HTC results show a strong linkage of the TNF-alpha 5.5 kb allele with DR types in particular with A1B8DR3. This tight linkage of TNF-alpha alleles with extended haplotypes and the significant increase of heterozygotes in patients could lead to some explanation of the DR3 association with a variety of autoimmune diseases particularly IDDM.
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PMID:TNF-alpha gene polymorphisms: association with type I (insulin-dependent) diabetes mellitus. 257 13

The particular susceptibility to insulin-dependent diabetes mellitus (IDDM) conferred by HLA-DR3,4 heterozygosity has been suggested to be an effect of transcomplementation of HLA class II molecules. To test this hypothesis of special IDDM-specific hybrid determinants and to evaluate the T-cell repertoire towards a specific antigen in IDDM patients we generated a total of 352 PPD-specific T-cell lines by the soft-agar cloning technique and studied their restriction by HLA class II molecules. Of these lines, 227 were from nine IDDM patients, of whom six were DR3,4 heterozygotes, and 125 from 10 healthy controls. Forty-six T-cell lines elicited specific responses in at least two experiments and in addition to T-cell lines demonstrating class-II-restricted PPD specificity, lines with an alloreactivity occurred. HLA-DQ-restricted PPD-specific T-cell lines were not identified and a possible DP restriction (DPw2) was only observed with one line. These data indicate that PPD is preferentially presented to T cells in the context of HLA-DR/Dw. Presentation of PPD by hybrid molecules in IDDM patients or by IDDM-specific class II epitopes recognized by the T-cell lines was not demonstrated. By restriction fragment length polymorphism analysis using a probe for the joining region of the T-cell receptor gamma gene, T-cell lines generated by the soft-agar cloning technique were found to be oligoclonal. It is concluded that soft-agar cloning should be followed by subsequent limiting dilution in order to assure monoclonality. Different preparations of antigen-presenting cells (APC) were tested. In several cases the T-cell lines were not able to respond to PPD presented by Epstein-Barr-virus-transformed lymphoblastoid cell lines (LCL). It was demonstrated that lipopolysaccharides (LPS) of E. coli potently reduce the proliferative response of antigen-specific and alloreactive T cells when T-cell-depleted peripheral blood mononuclear cells (E- cells) were used as APC, whereas only limited inhibition was observed when LCL were used as APC in the presence of LPS. This effect of LPS is suggested to be mediated by increased prostaglandin secretion by monocytes among the E- cells since indomethacin abolished the effect of LPS. This observation may have implications for T-cell cloning procedures since we have found that most commercially available culture media are heavily contaminated with endotoxin.
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PMID:Characterization of PPD-specific T-cell lines generated in type I (insulin-dependent) diabetic and healthy individuals. 258 37

Thirty Ethiopian malnutrition-related diabetes mellitus (MRDM) patients were HLA typed and their HLA antigen frequencies were compared to those of 31 previously typed insulin-dependent diabetes mellitus (IDDM) patients and to 84 controls from the same ethnic background. In comparison to controls, a striking association between MRDM and HLA-DR3 (X2 = 15.15, p = 0.0001) was observed, whereas the frequency of HLA-DR4 was non-significantly increased (RR = 1.72). The frequency of DR2, DQw1, and DQw6 was decreased among MRDM. In comparison to IDDM that is associated with both DR3 and DR4 in this population, MRDM showed no significant differences in HLA class II antigens frequencies. Therefore, the genetic basis of susceptibility to MRDM and IDMM in Ethiopia is at least partially identical.
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PMID:HLA-DR and -DQ antigens in malnutrition-related diabetes mellitus in Ethiopians: a clue to its etiology? 262 60

Physicians in the State of Wisconsin were contacted by mail and asked to report all cases of diabetes in patients under 20 yr diagnosed between 1 July 1982 and 30 June 1984 in order to study factors associated with seasonality in insulin-dependent diabetes mellitus (IDDM). Wisconsin's population is fairly homogeneous and is primarily middle socioeconomic class, small-town or rural, and of northern European Caucasian descent. The incidence of IDDM in winter was higher than in summer during the first year of the study, similarly to results of other studies. However, there was no significant winter peak in diagnosis during the second year. When monthly incidence rates from both years were combined, the increased evidence of IDDM in winter vs. summer was evident in males, but not in females. There appeared to be a spike in the number of new cases of IDDM in the first year of the study which was more evident in males. Such a spike is consistent with spikes in the incidence of IDDM occurring about the same time in Europe and in North America. The percentage of patients with antibody titres to Coxsackie virus and mycoplasma pneumoniae diagnosed during the first winter's peak were equal to those in nondiabetic controls. The distributions of HLA DR types of patients diagnosed in winter were no different from diabetics diagnosed in other seasons. The distribution of HLA DR types (5% DR2, 55% DR3, 82% DR4 and 38% DR3DR4) were similar to those of other groups of Caucasian subjects with IDDM. Also similarly to other studies of IDDM, 14% of the patients had thyroid microsomal antibody titers. The results of this study support the previously-advanced idea that winter might precipitate overt carbohydrate intolerance in individuals in whom insulin cell destruction is already well established (Diabetes, 36, 265-268, 1987). If this is true, studies of seasonality in IDDM might not be informative about the causation of IDDM.
Diabetes Res 1989 Dec
PMID:Epidemiology of insulin dependent diabetes before age 20 in Wisconsin, with particular reference to seasonality. 263 92

A Norwegian family showed 20 cases of verified or suspected diabetes in 5 generations, 13 being females and 7 males. In 12 patients the diagnosis was established at 26 years of age or earlier. Fourteen patients were definitely non-insulin-dependent. A high frequency of severe diabetic ophthalmopathy was noted, five patients were blind, two had proliferative retinopathy, and one simplex retinopathy and cataract. Five patients from the last 3 generations were islet cell antibody negative and C-peptide positive. In selected patients the serum insulin response to oral glucose was markedly reduced. HLA determinations in these patients showed absence of DR3 and DR4, and presence of DR2. The inheritance of diabetes in this family is compatible with an autosomal, dominant trait, and the majority of cases fulfilled the criteria of maturity-onset diabetes of the young. The high frequency of severe ophthalmopathy underscores that this disease may have an unfavourable evolution.
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PMID:Maturity-onset diabetes of the young. Studies in a Norwegian family. 264 41


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