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)

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

HLA typing was done in 25 cases of insulin dependent diabetes mellitus (IDDM) and compared with 60 healthy controls. There was a significantly increased frequency of HLA B-8, HLA B-12 and HLA DR-3 in IDDMO. The odds ratio (relative risk) of developing IDDM for HLA B-8 was 4.42 (p less than 0.10), for HLA B-12 was 3.56 (p less than 0.10) and for HLA DR3 9.75 (p less than 0.001). There was no correlation of HLA specificity with complications of diabetes.
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PMID:Human leucocyte antigen and insulin dependent diabetes mellitus. 172 75

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

Insulin-dependent diabetes mellitus is common in Tunisia. Eighty-six pediatric cases managed at the diabetes clinic of a department of pediatrics in Tunis from 1979 through 1989 were studied. Relevant clinical and biological findings were abstracted from case-records. Admissions of patients with diabetes mellitus accounted for approximately 0.44% of admissions to the pediatric ward during the study period. Mean age of patients was 7 years. Sex ratio was 0.89. Polyuria with polydipsia and ketoacidosis were the two most common presenting manifestations. Mean blood glucose level at diagnosis was 22.44 mmol/l. Rate of consanguinity was 48%. HLA typing studies demonstrated a high prevalence of DR3 and DR4 alleles and especially of simultaneous expression of both these alleles. Several factors are incriminated in the development of childhood insulin-dependent diabetes mellitus.
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PMID:[An analytic study of cases of childhood diabetes in a pediatric department in Tunis]. 175 Jul 45

An analysis of the HLA-types of 351 children in whom a diagnosis of insulin dependent diabetes mellitus (IDDM) had been made between 1960 and 1990 revealed that although the frequencies of HLA-DR3, -DR4, -DR3/4, -B8 and -Bw62 were increased there was, depending on the year of diagnosis, a marked fluctuation in the frequencies of these HLA-antigens and in the frequency with which -B8 was associated with -DR3 and -Bw62 with -DR4 suggesting heterogeneity/variation in agents initiating/triggering IDDM.
Diabetes Res 1991 Apr
PMID:Frequencies of HLA-DR3, -DR4, -B8 and -Bw62 in diabetic children diagnosed between 1960 and 1990. 180 81

Genetic factors are essential to the occurrence of insulin-dependent diabetes (IDD) and non-insulin-dependent diabetes (NIDD), and all that environmental factors do is facilitate the development of diabetes in genetically predisposed subjects. Recent advances in molecular biology have improved our understanding of diabetic heredity. IDD is closely linked to the HLA region of chromosome 6. Ninety percent of IDD belong to the DR3 or DR4 group. The occurrence of IDD is facilitated by a peculiar conformation of the HLA DQ molecule which permits the presentation of antigens to the T-cells. Other genes still have to be discovered since IDD seems to be of polygenic origin. NIDD is even more "hereditary" than IDD, but owing to the lack of an unquestionable marker the responsible genes cannot be located with certainty. Several possible genes such as those of insulin, insulin receptor and glucose transporter, are suspected, at least in some forms of NIDD--a clinically and biologically highly heterogeneous disease. Widespread family studies should, in a not too distant future, locate the responsible gene thereby leading to early detection or even prevention of NIDD.
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PMID:[Diabetes and heredity]. 185 94

To ascertain why HLA-DR2 seems to confer only a moderate resistance to insulin-dependent diabetes mellitus (IDDM) in the high-incidence population of Sardinia, Italy, 32 families having one individual affected with IDDM (the proband) and 31 families without IDDM history were randomly selected from the same geographical area and serologically and molecularly HLA typed. The 64 haplotypes of the probands were then compared with the 122 haplotypes determined in the parents from the control families. Two haplotypes were found to have the highest percentage in the general population (12.3% and 7.3%, respectively). The first is the already described "Sardinian" extended haplotype A30, Cw5, B18, 3F130, DR3, DRw52, DQw2 (39.0% in IDDM patients). The second is an extended haplotype that has not been identified before (A2, Cw7, B17, 3F31, DR2, DQw1), and, due to the DR2 allele, we expected it to be decreased in IDDM. However, a stratified analysis performed by removing the DR3 and DR4 haplotypes showed that the frequency of this haplotype is significantly increased in IDDM patients. A peculiar feature of this haplotype is its DQw1 allele, which is DQB1*0502 and has serine in position 57 of the DQ beta chain. The absence of an aspartic acid in this position seems to confer susceptibility to IDDM and not resistance. The fact that DQB1*0502 was present in 75% of the Sardinian DR2 haplotypes may explain why, in Sardinia, DR2 is not providing the commonly recognized resistance to IDDM.
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PMID:A new HLA-DR2 extended haplotype is involved in insulin-dependent diabetes mellitus susceptibility. 189 17

Studies of various insulin-dependent diabetes mellitus (IDDM) populations have shown that certain HLA antigens confer a high risk of developing disease. There is very little information concerning the distribution of HLA antigens in type 1 diabetes in the Turkish population. In this study, the HLA types of 75 patients and 50 controls were investigated. HLA-DR3 and HLA-DR4 were found more frequently in the IDDM cases (p = 0.0018 and 0.0119, respectively). DR3/DR4, although more frequent, did not achieve statistical significance. The decreased frequencies of DR1 and DR2 in the IDDM population were not significant whereas the DR7 was found to be significantly decreased (p = 0.025). The younger age of onset was strongly associated with DR4 (p = 0.0029). DR3 was more common among the male and DR4 in the female patients. However, the differences were not significant.
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PMID:The type 1 diabetes and HLA-DR in Turkey. 191 1

The aetiology of insulin-dependent diabetes (IDDM) involves genetic predisposition, a major component of which has been mapped in the HLA complex, near to or identical with genes encoding class II molecules. In Caucasian populations IDDM is strongly associated with the serologically defined HLA-DR3 and DR4 antigens, which are widely recognised as markers of susceptibility. The particularly high risk of DR3/DR4 heterozygotes suggests that susceptibility is determined by two genes acting synergistically. The development of recombinant DNA technology has allowed a finer description of the class II region and provided evidence that DQ rather than DR determinants may primarily influence IDDM susceptibility. The search for specific structural changes of the DQA and DQB genes has shown that susceptibility correlates with the absence of aspartic acid at position 57 on the DQ beta chain (DQ beta 57 Asp--) and/or the presence of arginine at position 52 on the DQ alpha chain (DQ alpha 52 Arg+). In Caucasians the formation of a putative DQ susceptibility molecule (DQ alpha 52 Arg+, DQ beta 57 Asp-) accounts best for the disease associations when transcomplementation molecules consisting of DQ alpha and beta chains encoded by different haplotypes are postulated to explain the excess risk of heterozygotes. The HLA-IDDM associations in the Japanese, however, are not explained by this model. These and other unresolved questions indicate that other residues of the DQ alpha and beta chains or other class II molecules (DR beta chains), as well as non-MHC genes, may also contribute to the susceptibility.
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PMID:The role of genetic predisposition to type I (insulin-dependent) diabetes mellitus. 193 Sep 40


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