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 restriction fragment length polymorphism (RFLP) of DQ beta was assessed in a panel of control and insulin-dependent diabetes (IDD) patients who were serologically typed as HLA-DR4 homozygotes or HLA-DR3, DR4 heterozygotes. Digestions of genomic DNA with Bam HI, Bgl II, Pst I, Xba I, and Hind III revealed a total of 15 RFLPs in the panel of 71 HLA-DR4 chromosomes. These RFLPs were organized into six allelic groups on the basis of segregation analysis in families. Complete RFLP haplotypes for the 5 restriction enzymes could be constructed for 42 of the HLA-DR4 chromosomes. This analysis revealed 18 RFLP haplotypes of DQ beta associated with the DR4 chromosomes tested. Two of these haplotypes, designated DQ3.DR4. a and DQ3.DR4.b, accounted for over 50% of the DR4 chromosomes analyzed. These two haplotypes were antithetical for the RFLPs detected by all five enzymes, indicating that they represent very distinct forms of DQ beta. The remaining 16 haplotypes were infrequent or unique and were closely related to either a DQ3.DR4.a or DQ3.DR4.b. Two of the RFLPs detected, a 5.8 kb Bgl II fragment and a 10.5 kb Bam HI fragment, had increased frequencies in disease-associated chromosomes. However, none of the RFLPs we detected exhibited a statistically significant increase in IDD or control populations. In contrast, the DQ3.DR4.b DQ beta haplotype was significantly decreased in IDD-associated DR4 chromosomes (P = 0.04). These results suggest that the DQ3.DR4.b DQ beta allele may be protective for the development of IDD.
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PMID:Polymorphisms of DQ beta genes in HLA-DR4 haplotypes from healthy and diabetic individuals. 288 84

A BamHI 3.7-kilobase (kb) fragment detected by an HLA-DQ beta-chain complementary DNA (cDNA) probe and negatively associated with insulin-dependent diabetes mellitus (IDDM) was cloned and sequenced to localize the polymorphism to BamHI sites in intervening sequences of an HLA-DQ beta-chain gene. A probe of the first intervening sequence (IVS 1) showed the BamHI 3.7-kb fragment in 6 of 17 HLA-DR3/4 controls but in 0 of 13 DR-identical IDDM patients. All IDDM patients (13 of 13) had BamHI fragments of 12 and 4 kb, detected in 9 of 17 controls (P less than 0.02). The simple restriction fragment length polymorphism pattern of the IVS 1 probe was exploited by comparing 113 IDDM patients with 177 healthy controls to show increased prevalences in IDDM of the 12-kb (P less than 0.0001) and 4-kb (P less than 0.0001) fragments. In IDDM patients younger than 20 yr at onset, 98% were 12- and/or 4-kb positive, compared with 63% of controls (P less than 0.0001), giving a relative risk of 91.8 for individuals with both fragments. The 12-kb fragment was linked to HLA-DR4, and the 4-kb fragment to HLA-DR3. Both serologic markers were split and a non-DR3/non-DR4 IDDM patient was 4-kb positive. HLA-DQ seems therefore closer, than HLA-DR, to an IDDM susceptibility gene.
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PMID:Molecular cloning of a polymorphic DNA endonuclease fragment associates insulin-dependent diabetes mellitus with HLA-DQ. 288 47

DNA restriction fragments of the genes encoding HLA class II-beta antigens were compared in 34 patients with insulin-dependent diabetes mellitus and 34 HLA-DR-matched healthy individuals. Ninety-three fragments, determined by six restriction enzymes (EcoRI, EcoRV, HindIII, BamHI, Pvu II, and Taq I), were analyzed: (i) A DR Taq I 12.7-kilobase-pair fragment might be a marker for the extended haplotype HLA-B8, DR3. (ii) In controls, DR4 haplotypes are associated with two distinct clusters of DQ restriction fragments (DQR4 and DQR5). Almost all (94%) DR4 patients belong to the DQR4 and not to the DQR5 cluster. This suggests that, among HLA-DR4 haplotypes, only DQR4 haplotypes are involved in susceptibility to insulin-dependent diabetes mellitus. (iii) A DR Taq I 14.5-kilobase-pair fragment was found to be strongly associated with DQR4, mainly in DR3/DR4 heterozygous patients (P = 5 X 10(-4). However, these results must be interpreted with caution, taking into account the high number of statistical tests performed.
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PMID:A systematic study of HLA class II-beta DNA restriction fragments in insulin-dependent diabetes mellitus. 298 20

Type I (insulin dependent) diabetes is usually believed to present acutely and it is assumed that metabolic decompensation is sudden. In a prospective family study, however, 10 of 13 subjects developing the disease showed progressive or intermittent development of hyperglycaemia over many months and the others had non-specific symptoms over a long period. All were first degree relatives of a child with type I diabetes; 10 were siblings (aged 5-24) and three were parents (aged 45-58). All possessed HLA-DR4 or DR3, or both, and all but two had been positive for islet cell antibodies for six to 86 months before diagnosis. Ten had non-specific symptoms for two to 14 months before the onset of thirst and polyuria; one remained asymptomatic even when insulin became necessary. Six subjects had an oral glucose tolerance test before clinical onset, of whom five were diabetic by World Health Organisation criteria four, four, six, seven, and 21 months before insulin was needed. Nine showed random blood glucose concentrations above the 97.5th centile (6.3 mmol/l) six to 34 months (median 12) before diagnosis. Two others had a glucose tolerance test result compatible with diabetes but had not reached the stage of needing insulin. Hyperglycaemia is often of insidious onset in type I diabetes, even in children and young adults. Diagnosis will inevitably be late if considered only when acute symptoms of thirst and polyuria develop.
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PMID:Type I (insulin dependent) diabetes: a disease of slow clinical onset? 310 66

It is well established that the HLA-DR3 and HLA-DR4 genes at the HLA-DR locus on chromosome 6 are strongly associated with increased susceptibility to insulin-dependent diabetes, and that the predisposition is greatest among individuals who possess both of these genes (that is, are HLA-DR3/4 heterozygotes). We report evidence from our Alberta study that the HLA-DR1 gene is also associated with increased susceptibility, primarily when it occurs in heterozygous combination with HLA-DR4 (frequency of HLA-DR1/4 heterozygotes among diabetics: expected = 3%, observed = 11%, p = 0.03). In addition, we report evidence that genes in the region of the GM locus on chromosome 14 also influence susceptibility by interacting with HLA-DR region genes. Alberta diabetics who were HLA-DR3/4 heterozygotes had an increased frequency of the G1m(1) antigen and the G1m(2) antigen compared with non-DR3/4 diabetics; the latter increase was statistically significant (p = .025). When data from all three previously published studies, our Alberta study, and an unpublished American study were pooled. HLA-DR3/4 diabetics had significantly increased frequencies of both G1m(1) (p = 0.001) and G1m(2) (p = 0.014). Finally, we report possible evidence (not statistically significant) that genes in the region of the KM locus on chromosome 2 may exert HLA-dependent effects on susceptibility to diabetes: in our Alberta study and the one other study which employed control subjects, DR4-positive diabetics had higher frequencies of Km(1) than either DR4-positive controls or DR4-negative diabetics.
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PMID:The genetics of susceptibility to insulin-dependent diabetes mellitus--possible new markers. 311 66

The epidemiology of Type 1 (insulin-dependent) diabetes was studied during a period starting after an unusually sharp epidemic of mumps. The number of diabetic cases increased significantly 2-4 years after the epidemic. Incidence rates were highest in geographical areas with the highest incidence of mumps and lowest in areas with the smallest numbers of reported mumps cases. Serological studies employing EIA-assays indicated recent mumps infections more often among newly diagnosed diabetic children than among matched controls although the incidence was low (13% of patients and 4% of controls had serological markers of recent mumps). Those patients, who had had serologically verified recent mumps had more often HLA-DR4 associated risk antigens (Dw4 and Dw14) than other patients. Also clinical history of mumps was obtained more often from diabetic children than from controls as 27% of the patients and 14% of the controls had had clinical mumps during the five years preceding the diagnosis of diabetes. These results confirm several earlier reports suggesting a connection between mumps and Type 1 diabetes and that the onset of diabetes may be delayed by several years.
Diabetes Res 1988 Nov
PMID:Mumps infections in the etiology of type 1 (insulin-dependent) diabetes. 324 43

We have shown in previous studies that the TA10-subtype of HLA-DQw3 is significantly increased in HLA-DR4 type I (insulin-dependent) diabetic patients. Data presented in this article indicate that this association only occurs in heterozygous DR3/4 patients and not in DR1/4 patients. Because there is an interactive effect of both DR3/4 and DR1/4 in type I diabetes, the data indicate that the contribution of DR4 haplotypes varies depending on the haplotype borne on the homologous chromosome. In addition, the frequency of the B44-DR4 haplotype was shown to be decreased in DQw3 (TA10-) diabetic subjects who were DR3/4 compared with those who were DR1/4 or DR4/x (a pooled group of patients with different DR alleles). This finding suggests that the decrease in the B44-DR4 haplotype in type I diabetes is not solely dependent on its linkage disequilibrium with the DQw3 (TA10+) allele but suggests there is an additional effect exerted independently.
Diabetes 1988 Jul
PMID:Association of HLA-DQw3 (TA10-) with type I diabetes occurs with DR3/4 but not DR1/4 patients. 326 Feb 1

In most populations studied, HLA-DR4, a DRB1 (formerly DR beta I) allele, is increased in frequency among patients with insulin-dependent diabetes mellitus (IDDM). Using T-cells, one can distinguish five subtypes of DR4 (Dw4, Dw10, Dw13, Dw14, and Dw15). Two of these (Dw4 and Dw10) are IDDM-associated in the populations studied here. Therefore, Dw4 and Dw10 could be causative or merely markers for a linked diabetes allele. If they are causative, one might expect them to share some unique structural element or at least to associate consistently with IDDM in different populations. Published sequence data show no structural element unique to Dw4 and Dw10; moreover, the associations of these DR4-Dw subtypes with diabetes vary considerably in different populations. Thus the DRB1 locus probably cannot account for the DR4 association in IDDM. The strong linkage disequilibrium between IDDM and Dw4 and Dw10 suggests that the diabetes susceptibility locus should be in the vicinity of the DR region or the DQ region of the HLA complex. Alternative hypotheses are discussed, relating DR- and DQ-region alleles to IDDM. We further postulate that the evolutionary event that produced the Dw10 allele occurred on a Dw4 haplotype that happened to carry a diabetes susceptibility allele at another locus.
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PMID:T-cell-defined DR4 subtypes as markers for type 1 diabetes. 326 May 86

Children with newly diagnosed insulin-dependent diabetes mellitus (IDDM) had increased numbers of CD25 positive lymphocytes in peripheral blood and peripheral blood mononuclear cells responded to insulin antigens by proliferation. The CD25 positivity and insulin proliferation were associated to the duration of symptoms before the diagnosis of IDDM. Thus increased numbers of CD25 positive cells were found in 89% and insulin induced proliferation in 100% of patients with symptoms of diabetes of less than 1 week's duration before diagnosis, while CD25 positivity and insulin-induced proliferation were observed in 36% and 29% of children who had had symptoms for 4 weeks or more before diagnosis. Children with IDDM also had increased numbers of CD4 positive T cells in peripheral blood. The frequency of HLA-DR4 and HLA-DR3/4 in diabetic children was higher and that of HLA-DR2 lower than in the normal population. Insulin, islet cell, gastric-parietal cell, thyroid and antinuclear antibodies did not correlate to the duration of symptoms before diagnosis.
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PMID:Insulin responses and lymphocyte subclasses in children with newly diagnosed insulin-dependent diabetes. 328 Jan 82

A family is reported in which the mother and both of her children developed insulin-dependent diabetes mellitus between 9 and 19 months of age, reflecting the importance of heredity in the natural history of this disease. That overt complications of diabetes were not present in any of the individuals, and that blood sugars were maintained close to normal on relatively small amounts of exogenous insulin, suggests a protective function in these patients related to residual secretion of insulin by beta cells. Human lymphocyte antigen (HLA) typing in this family showed that, although the diabetic children had identical HLA types, neither the mother nor her children possessed the diabetes-associated antigen HLA-DR3 or HLA-DR4. This raises the possibility that selective loss of diabetes-susceptible fetuses (suggested to be responsible for the low risk of diabetic mothers producing diabetic offspring) may be influenced by the HLA type of the mother.
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PMID:Diminished complications in a non DR3 DR4 family with insulin-dependent diabetes. 331 68


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