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 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

We describe the characteristics of 75 Arab Type 2 diabetic patients in Kuwait. Their age (+/- SD) at onset was 41 +/- 10 years, and fasting serum C-peptide concentration was 0.32 +/- 0.23 nmol/l (n = 51). Fifty-three percent (37/70) possessed HLA-DR3 or -DR4 epitopes, and 64% (47/73) had a family history of diabetes. Data review suggested that they could be segregated into two groups, those under 40 years old at onset (32 +/- 6 years, n = 37), and the remainder (48 +/- 6 years, n = 38) (p less than 0.001). Those in the former group had a significantly higher frequency of a family history of diabetes than those in the latter group (92% vs 38%, p less than 0.001) suggestive of a greater genetic influence on the development of Type 2 diabetes in those with early onset disease.
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PMID:Type 2 diabetes in Arab patients in Kuwait. 296 43

A polymorphic DNA sequence in the 5'-flanking region of the human insulin gene was studied in relation to Type 1 (insulin-dependent) diabetes. In 141 Caucasoid subjects analysed by Southern blot hybridisation techniques, two major DNA insertions were observed: a Class 1 allele or a Class 3 allele. The Class 2 allele was not observed in this group of subjects. Genotype frequencies in a control population (n = 88) were: homozygous 1/1, 42%; heterozygous 1/3, 50%; and homozygous 3/3, 8%. Corresponding genotype frequencies in 53 Type 1 diabetic patients were 79%, 21% and 0%, respectively (p less than 0.0005 from chi 2 test). This confirms prevalence data reported by Bell et al. [16]. There appeared to be no coinheritance with HLA-DR3/DR4 related antigens, nor with autoimmune features. Analysis of 17 Type 1 diabetic pedigrees including 34 diabetic and 69 non-diabetic subjects did not demonstrate genetic linkage of these DNA inserts with diabetes, using an autosomal recessive, single locus model of inheritance.
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PMID:Type 1 (insulin-dependent) diabetes and a highly variable locus close to the insulin gene on chromosome 11. 299 Oct 52

To study the relationships between the responses to viral antigens and the HLA-DR3 and -DR4 associations in Type 1 (insulin-dependent) diabetes mellitus, the frequency of T-lymphocyte proliferating in response to mumps, Coxsackie B4 and varicella-zoster antigens was determined. A decreased frequency was found in T lymphocytes able to respond to mumps or Coxsackie B4 when presented together with DR3, as compared with the frequency of T lymphocytes able to respond to these viruses together with other DR determinants. This was not found for varicella-zoster or purified protein derivative of tuberculin. In contrast, an increased frequency was found in T lymphocytes responding to mumps or Coxsackie B4 together with DR4, compared with other DR determinants. The results were similar in Type 1 diabetic and healthy individuals. The results suggest that elements on the DR3 and DR4 molecules may control T-lymphocyte responses to mumps and Coxsackie B4 viruses.
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PMID:HLA-DR3 and -DR4 control T-lymphocyte responses to mumps and Coxsackie B4 virus: studies on patients with type 1 (insulin-dependent) diabetes and healthy subjects. 299 83

Although some previous studies have suggested that insulin-dependent diabetes mellitus (IDDM) is a heterogeneous condition with variant forms being associated with HLA-DR types, the evidence, thus far, is conflicting. To address this issue, we have examined the presenting characteristics of a consecutive admission series of 200 newly diagnosed cases of IDDM from the Children's Hospital of Pittsburgh. Because HLA-DR frequencies vary by race, data are presented only for the 172 white cases with complete HLA-DR typing. HLA-DR3 was found more frequently among male cases and DR4 among female cases (P less than 0.005). Generally, patients with DR4 presented with a severer clinical picture, being more likely to have impaired consciousness and significant dehydration. In addition, patients with DR4 were more likely to be acidotic, ketotic, and to more frequently report a recent viral infection. This latter finding was supported by a greater frequency of antibodies to Coxsackie-B viruses in the DR4 cases at presentation. These results therefore suggest that there is considerable heterogeneity in IDDM, at least in presenting characteristics, according to HLA-DR type.
Diabetes 1985 Dec
PMID:HLA heterogeneity of insulin-dependent diabetes mellitus at diagnosis. The Pittsburgh IDDM study. 299 11

Three HLA-DR beta genes were isolated from a Swedish HLA-DR3/4 insulin-dependent diabetes mellitus (IDDM) patient and characterized by restriction endonuclease mapping and nucleotide sequence analysis. Two out of the three DNA sequences differed from those of published DR beta-chain sequences. A DR beta-gene probe prepared from exon 4 and flanking sequences was used in a Southern blot analysis of blood donors' DNA and DNA from HLA-DR3/4 IDDM patients and HLA-DR-matched healthy control subjects. This probe differentiated HLA-DR3/4 IDDM patients and HLA-DR-matched controls in the Scandinavian population but not in the North American Caucasoid population.
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PMID:Characterization of three HLA-DR beta genes isolated from an HLA-DR 3/4 insulin-dependent diabetic patient. 301 88

From 11 studies, a total of 1,792 Caucasian probands with insulin-dependent diabetes mellitus (IDDM) are analyzed. Antigen genotype frequencies in patients, transmission from affected parents to affected children, and the relative frequencies of HLA-DR3 and -DR4 homozygous patients all indicate that DR3 predisposes in a "recessive"-like and DR4 in a "dominant"-like or "intermediate" fashion, after allowing for the DR3/DR4 synergistic effect. Removal of DR3 and DR4 reveals an overall protective effect of DR2, predisposing effects of DR1 and DRw8, and a slight protective effect of DR5 and a predisposing effect of DRw6. Analysis of affected-parent-to-affected-child data indicates that a subset of DR2 may predispose. The non-DR3, non-DR4 antigens are not independently associated with DR3 and DR4; the largest effect is a deficiency of DR2, followed by excesses of DR1, DRw8, and DRw6, in DR4 individuals, as compared with DR3 individuals. HLA-B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. The presence or absence of Asp at position 57 of the DQ beta gene, recently implicated in IDDM predisposition, is not by itself sufficient to explain the inheritance of IDDM. At a minimum, the distinguishing features of the DR3-associated and DR4-associated predisposition remain to be identified at the molecular level. Risk estimates for sibs of probands are calculated based on an overall sibling risk of 6%; estimates for those sharing two, one, or zero haplotypes are 12.9%, 4.5%, and 1.8%, respectively. Risk estimates subdivided by the DR type of the proband are also calculated, the highest being 19.2% for sibs sharing two haplotypes with a DR3/DR4 proband.
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PMID:Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. 305 85

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

In the genetically homogeneous Danish population, 27 HLA-DR3,4 heterozygous patients with insulin-dependent diabetes mellitus (IDDM) and 19 DR3,4 heterozygous controls without family history of IDDM were investigated for HLA-region markers and Gm and Km immunoglobulin allotypes. The aim was to define susceptibility factors for IDDM development other than HLA-DR using a number of techniques: lymphocytotoxicity (HLA-DR and DQ antigens), cellular methods (Dw and DP typing), restriction fragment length polymorphism (DQ alleles), electrophoresis and immunofixation (BF and C4 allotypes), and passive hemagglutination inhibition (Gm and Km immunoglobulin allotypes). The complement allotype C4A3 and the HLA-DQw8 (DQw3.2) antigen were found in all of the patients, whereas this was the case for only 8 of the 19 controls (P = 6 x 10(-6)): five lacked C4A3, five others lacked DQw8, and one of the controls lacked both of these factors. Fourteen of the patients had the complement allotype C4B3 versus three of the controls (P = 0.01). Previously reported family studies suggest that these alleles are part of the following haplotype: B15, BFS, C4A3, C4B3, DR4, Dw4, DQw8, and these factors were found together in ten of the patients versus one of the controls (P = 0.01). The markers usually associated with DR3 did not show significant differences between IDDM patients and controls, and the non-HLA markers studied showed no significant deviation from what was expected. In addition to the susceptibility factor DQw8, the study suggests the existence of susceptibility genes for IDDM near the complement C4 genes on DR4-carrying haplotypes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The susceptibility to insulin-dependent diabetes mellitus is associated with C4 allotypes independently of the association with HLA-DQ alleles in HLA-DR3,4 heterozygotes. 313 57


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