Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analysis of the frequencies of class II HLA-DR and HLA-DQ alleles by serological and DNA typing in 49 Japanese patients with type 1 (insulin-dependent) diabetes and 31 Japanese controls indicates the following. (i) Susceptibility is more strongly associated with the HLA-DQ subregion than with the HLA-DR subregion. (ii) Of the class II alleles detected, the A3 allele of the DQA1 locus was the most strongly associated with disease. Ninety-six percent of the patients were positive for the A3 allele compared to 53% of the controls (P = 0.001; relative risk = 19.7; confidence limits = 3.72-188.64). (iii) The DQw8 allele of the DQB1 locus, which is associated with susceptibility to type 1 diabetes in Caucasians and Blacks, was not increased in frequency in Japanese patients (22%) versus controls (19%). (iv) Asp-57-encoding DQB1 alleles are associated with reduced susceptibility to type 1 diabetes in Caucasians. The major predisposing haplotypes in Japanese are DR4 and DR9. By DNA sequence analysis, both of these Japanese haplotypes have Asp-57-encoding DQB1 alleles. Oligonucleotide dot blot analysis showed that all, except 1, of the 49 Japanese patients and all of the 31 controls have at least one Asp-57-encoding DQB1 allele. In addition, 40% of the patients were homozygous for Asp-57-encoding DQB1 alleles versus 35% of the controls. The high frequencies of Asp-57-encoding DQB1 alleles in this ethnic group may account for the rarity of type 1 diabetes in Japan.
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PMID:The A3 allele of the HLA-DQA1 locus is associated with susceptibility to type 1 diabetes in Japanese. 230 May 72

Restriction fragment length polymorphism using an HLA-DQ beta-chain genomic probe showed that 63 children with insulin-dependent (type 1) diabetes mellitus (IDDM) were all (100%) positive for the BamH1 fragments 12 kb and/or 4 kb compared to 98% (62/63) for HLA-DR3 and/or 4 and 75% (47/63) for HLA-B8 and/or 15. The 36 (56%) DR3-positive children were all 4-kb-positive; however, a total of 44 (70%) children were 4-kb-positive (P less than 0.02). The 55 (87%) DR4-positive children were all 12-kb-positive, but a total of 56 (89%) were 12-kb-positive (NS). The heterozygosity at the HLA region increased from 11/63 (18%) for HLA-B8/15 to 29/63 (46%) for HLA-DR3/4 (P less than 0.0004) and to 37/63 (59%) for the HLA-DQ 4 kb/12 kb fragments (P less than 0.02). The test of an equal probability of a positive result under the adjacent pair of tests indicates that the increased risk of developing IDDM in association with HLA-DQ is to a great extent due to heterozygosity at this locus. There were no differences between the 4 kb/12 kb and the DR3/4-positive IDDM children with respect to fasting or meal-stimulated C peptide, insulin requirement, or levels of insulin antibodies formed during the first 12 months of insulin therapy. Our results support the hypothesis that HLA-DQ is closely associated with an increased risk of childhood IDDM, and when typed for at this locus parameters of the clinical course were homogeneous, suggesting that factors other than HLA-DQ may determine previously observed differences between IDDM children in clinical or functional parameters.
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PMID:HLA heterozygosity in insulin-dependent diabetes is most frequent at the DQ locus. 233 66

INSULIN-dependent (type I) diabetes mellitus (IDDM) follows an autoimmune destruction of the insulin-producing beta-cells of the pancreas. Family and population studies indicate that predisposition is probably polygenic. At least one susceptibility gene lies within the major histocompatibility complex and is closely linked to the genes encoding the class II antigens, HLA-DR and HLA-DQ (refs 3, 4). Fine mapping of susceptibility genes by linkage analysis in families is not feasible because of infrequent recombination (linkage disequilibrium) between the DR and DQ genes. Recombination events in the past, however, have occurred and generated distinct DR-DQ haplotypes, whose frequencies vary between races. DNA sequencing and oligonucleotide dot-blot analysis of class II genes from two race-specific haplotypes indicate that susceptibility to IDDM is closely linked to the DQA1 locus and suggest that both the DQB1 (ref. 7) and DQA1 genes contribute to disease predisposition.
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PMID:Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. 249 58

The genetic association between HLA-system and chronic lymphocytic thyroiditis (CLT) related or not to type I diabetes mellitus (IDDM), have been analysed in three groups of children: 16 with CLT, 9 with CLT and IDDM, 11 with IDDM and 200 normal controls. The DQw1 antigen (75% vs 55%) was found associated with CLT, furthermore the observed increase of DR1 and DR2 antigens (37% respectively) is secondary to the linkage disequilibrium that exists between them and DQw1. DR3 antigen (60%) was found significantly increased (p less than 0.001) in CLT patients compared with the control group (24%). In diabetic patients, DR3 and DR4 were found in 85% and 63% respectively (p less than 0.001). The DR3 associated haplotype in CLT patients was different from the diabetic one's. All the diabetics, but one, were DR3-B18 haplotype carriers, but this association was only found in 25% CLT patients. The titre of thyroid microsomal antibodies (MCHA) was more frequent in the patients with DQw1 antigen (MCHA DQw1+ : 1/1072; DQw1- : 1/606). The CLT predisposition in childhood may be influenced by genes located within the HLA-region probably more than one, different from the genes related to IDDM. One of this genes closed to the HLA-DQ region, will be involved in the production of autoantibodies.
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PMID:[Susceptibility to chronic HLA-system-associated lymphocytic thyroiditis. Its relationship with insulin-dependent diabetes mellitus]. 262 85

To investigate HLA-linked genes controlling the susceptibility and resistance to insulin dependent diabetes mellitus (IDDM), HLA-DQ alleles of 45 Japanese patients with IDDM were analysed, using sequence specific oligonucleotide (SSO). DQA1*0301 and DQB1*04 were positively associated (R.R = 6.6, Pc less than 0.05 and R.R. = 4.7 Pc less than 0.01) and DQA1*0103 and DQB1*0104 were negatively associated (R.R. = 0.2, Pc less than 0.01) with IDDM. DQA1*0103 and DQB1*0104 were in strong linkage disequilibrium to encode for DQw6 molecule. Therefore, in a Japanese population, the DQw6 molecule seems to control the resistance to IDDM. To determine whether or not the DQw6 molecule itself can protect against glycosuria and insulitis in NOD mice, these animals were mated with HLA-DQw6 transgenic-C57BL/6 mice (DQw6-B6) and the F1 progeny expressing the DQw6 molecule were backcrossed with NOD mice. Eighty-five female backcross progenies were classified into four groups, according to the MHC classII phenotype; I-ANOD/I-ANOD DQw6(-), I-ANOD/I-ANOD DQw6(+), I-ANOD/I-Ab DQw6(-) and I-ANOD/I-Ab DQw6(+). At the age of 16 weeks, 9.1% of the DQw6(-) I-Ab(-) mice had a glycosuria whereas none of the DQw6(+) I-Ab(-) mice had a glycosuria. At the age of 30 weeks 13.6% of the DQw6(-) I-Ab(-) mice had a glycosuria and 7.7% of the DQw6(+) I-Ab(-) mice had a glycosuria. Histological examinations of the pancreas were performed in the 30 week old mice or after the development of glycosuria.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glycosuria and insulitis in NOD mice expressing the HLA-DQw6 molecule. 270 41

Thirty-six consecutive paediatric patients (0-16 years old) with recently contracted juvenile diabetes (IDDM) during 1982-84 were included in the study. Sera were assayed for recent or current Coxsackie B virus (CBV) infection using a specific and sensitive IgM RIA. Eighteen patients (50%) had IgM against CBV 1-5. The patients were also assayed for restriction fragment length polymorphism (RFLP) patterns with DNA probes coding for HLA-DR and DQ beta chains. The CBV-positive patients (n = 18) had either RFLP patterns associated with HLA-DR 3 or 4 or HLA-DQ patterns III or IV beta. Two of the CBV negative patients had neither HLA-DR 3 nor DR 4 and four of them had neither DQ patterns III nor IV. Eleven out of 18 CBV-positive patients had HLA-DQ III and DR 3 (61%) versus 5 out of 18 (28%) of the CBV-negative patients. All 11 patients with serology positive for CBV 2, 3, and 5 had HLA-DR 4 and DQ IV patterns. This was significantly (P less than 0.01) different from all five CBV 4-positive patients, who in contrast all had HLA-DR 3 or HLA-DQ III patterns. CBV 1-positive patients (n = 2) all had HLA-DR 3, 4, and HLA-DQ III, IV patterns. Thus CBV 4 seems to be significantly associated with a different host genetic constitution from at any rate CBV 2, 3, and 5, and possibly CBV 1.
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PMID:Matching of host genotype and serotypes of Coxsackie B virus in the development of juvenile diabetes. 288 88

Associations of insulin dependent diabetes mellitus exist with the HLA-DR antigens DR3 and DR4 in both British Caucasoid and Dravidian subjects. However, it is only in British Caucasoids that an increased relative risk is found in those subjects who co-inherit both of these antigens. The nature of these HLA associations has been explored using Southern blot techniques and radioactive HLA-D region probes. In both populations the same DR4 related polymorphism was found in IDDM subjects whereas different HLA-DR3 preferential allelic associations were observed between British Caucasoid and Dravidian subjects. The best differentiation between diabetics and controls was found by a combination of HLA-DQ region alpha and beta polymorphisms which were totally different for the two populations. These data indicate that at least one gene involved in the susceptibility to IDDM is located within the HLA-DQ region and this may be related to HLA-DR4. The location of a DR3 related gene remains elusive and may be the DR beta gene encoding DR3 itself. In both populations it is a combination of two HLA-D region haplotypes which is strongly associated with IDDM leading to the possibility of trans complementation leading to the formation of mixed isotypic dimers.
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PMID:The genetic susceptibility to IDDM in British and south Indian subjects. 314 91

A five amino acids-long sequence (GPPAA) in the region of the 57th amino acid of HLA-DQ8 beta chain, which seems to be important in defining the risk for type 1 diabetes, occurs also in the BERF4-encoded EBNA3C protein of Epstein-Barr virus (EBV) in six successive repeats. The antigenicity of this region was analysed using synthetic peptides containing different modifications of the GPPAA sequence. Two of the seven individuals who had acute EBV infection produced antibodies against an EBV-derived peptide (GPPAAGPPAAGPPAA) paralleling the EBNA2 antibodies. These two cases also contracted type 1 diabetes immediately after the infection. High antibody levels against this peptide were found in a total of 12% of EBV+ individuals, and in most cases antibodies remained at high levels for several years. Human sera as well as affinity-purified antibodies specific for the GPPAAGPPAAGPPAA peptide reacted also with shorter peptide analogues (GPPAAGPPAA and GPPAA), as well as with peptides containing the surrounding motifs from DQ8 beta chains. However, none of these antibodies bound to denatured DQ8 beta chains in immunoblotting. The charge of the 57th amino acid modulated the antigenicity of this epitope, as peptides from Asp-57-negative DQ molecules were reactive, while peptides from Asp-57-positive DQ molecules were not. The responsiveness was seen in both HLA-DQ8-positive and -negative subjects as well as in type 1 diabetic individuals. The results suggest that some individuals who carry the GPPAA sequence in their HLA-DQ molecule recognize this epitope in EBV. This phenomenon may have potential importance in EBV-induced immune abnormalities, although cross-reactivity against DQ molecules could not be demonstrated in the present study.
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PMID:Antibody reactivity to an Epstein-Barr virus BERF4-encoded epitope occurring also in Asp-57 region of HLA-DQ8 beta chain. Childhood Diabetes in Finland Study Group. 750 47

IDDM is known to be associated with genes of HLA complex, particularly alleles of HLA-DQ. The 40-kb TAP gene complex is located approximately 150 kb centrometric to the DQB1 locus. The TAP1-TAP2 protein heterodimer is required for normal expression levels of class I, molecules on the surface of cells. While present evidence implicates HLA-DQ as the major susceptibility locus in IDDM, as class I expression apparently plays a role in the progression of disease, the possibility exists that the association attributed to HLA-DQ is in fact due to an association with the TAP genes. Several studies have concluded that the alleles of TAP1 are not significantly associated with IDDM; this report concentrates on the more telomeric TAP2 locus. During this investigation, six previously described TAP2 alleles were identified in 208 normal Caucasians and 241 Caucasian diabetics. Sequence analysis of cDNA clones identified a seventh allele of TAP2, TAP2*F, which contains an arginine-to-cystine interchange at amino acid position 651. Overall, our results indicate only a modest association of IDDM with TAP2; however, the newly described TAP2*F allele was found to be significantly increased in a modest subset of our large diabetic population. These data, generated from the same population of controls and diabetics we previously studied at all other relevant MHC loci, provide additional evidence that the HLA susceptibility to IDDM maps to HLA-DQ.
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PMID:TAP2 association with insulin-dependent diabetes mellitus is secondary to HLA-DQB1. 755 30

Fifty-five Danish families with two offspring concordant for type 1 diabetes--identified through a nationwide population-based survey, and 57 "true sporadic" cases--matched with familial cases for age at onset, but with no IDDM-affected first-degree relatives and long disease duration, and 110 control subjects were typed for putative genetic susceptibility markers for type 1 diabetes identified from a pathogenetic model. The markers included MHC class I, II and III loci, the manganese superoxide dismutase (MnSOD) locus (chr. 6q), interleukin-1 beta (IL1B), the IL-1 receptor antagonist (IL1RN), and the IL-1 type 1 receptor (IL1RI) loci (each chr. 2q). No significant differences between familial and sporadic cases were found within the MHC region (including the following loci: HLA-DQ, -DR, heat shock protein (HSP) 70, tumour necrosis factor (TNF), HLA-B and -A). In both groups of patients 11% were negative for both DQA1*0301-DQB1*0302 and DQA1*0501-DQB1*0201 genotypes, and 7% of the type 1 diabetics had genotypes unable to encode a susceptibility DQ alpha beta heterodimer. Disease association was found for the IL1RN (p = 0.04) and for the IL1RI (p = 0.03). When comparing controls and only familial cases with type 1 diabetes for the IL1RN polymorphism a difference was observed (p = 0.003). For the IL1B RFLP a trend for difference was observed between familial cases and control subjects (p = 0.046), whereas no differences between sporadic cases and control subjects could be demonstrated neither at the IL1B nor at the IL1RN loci. A difference in the MnSOD pattern was observed between sporadic cases and controls (p = 0.04).
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PMID:Genetic susceptibility markers in Danish patients with type 1 (insulin-dependent) diabetes--evidence for polygenicity in man. Danish Study Group of Diabetes in Childhood. 760 69


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