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

The allelic forms of the HLA-DQB gene have been recognized as susceptibility markers of type 1 diabetes mellitus. One of these alleles, the DQw3.2 (DQw8), accounts for the well-documented association of the DQw3 locus with the disease. This report describes a method using the polymerase chain reaction mismatch technique to amplify the three different DQw3 allele sequences in 26 insulin-dependent diabetic patients. Primers were designed that differed only at one base at the growing end of their sequences. Using a common oligonucleotide primer located downstream in the first domain of the DQB gene and three other primers located at the other end of the sequence being amplified, it was possible to identify and distinguish the DQw8 allele from the other two closely related alleles (DQw7, DQw9). This method, which could be useful in excluding HLA-related susceptibility to diabetes mellitus, is rapid and nonisotopic, and indeed could be adapted to investigate any DNA sequence polymorphism.
 ...
PMID:Use of the polymerase chain reaction mismatch technique to identify the HLA-DQw8 allele in patients with insulin-dependent diabetes mellitus. 172 61

We determined HLA types in 110 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) and studied the relationship between the HLA phenotypes and clinical features. Sixty-nine patients with insulin-dependent diabetes mellitus (IDDM) and 100 healthy blood donors served as controls. Concerning HLA DR and DQ loci, frequencies of DR4, DRw9 and DQw3.2 were higher, and those of DR2, DRw8, DRw11, DRw12 and DQw1 were lower in patients with IDDM compared than in healthy controls. There were no differences between NIDDM and normal controls in the frequency of a particular HLA DR antigen except for a decreased frequency in DRw11 in the former. The frequency of DQw3.2 antigen in NIDDM was intermediate between IDDM and normal controls. There were some differences between DQw3.2-positive and -negative NIDDM patients in clinical features. Those who showed low C-peptide responses during oral glucose tolerance test were more frequently found among DQw3.2-positive NIDDM patients. These results suggest that Type 1 diabetes mellitus may have a mild clinical course and is found among the Japanese NIDDM population.
 ...
PMID:Heterogeneity of non-insulin-dependent diabetes mellitus in HLA types and clinical features: comparison with insulin-dependent diabetes mellitus. 191 17

HLA Class II polymorphisms were analysed in 27 families with at least one Type I diabetic proband using Southern blotting technique according to 10th Histocompatibility Workshop Standards. The probes used were DRB, DQA1, DQB1 and DOB. We have studied 108 haplotypes and performed segregation analysis with HLA serology and restriction fragment length polymorphism (RFLP) data and compared "affected" with "non-affected" haplotypes (not inherited by IDDM patients). RFLPs correlated well with DR and DQ serology and detected additional polymorphisms. In particular, DQB polymorphism analysis showed segregation of the DQw3 splits with 88.5% of the DR4 affected haplotypes bearing the DQw3.2 split (now DQw8) and 11.5% the DQw3.1 split (now DQw7) while in the non-affected DR4 haplotypes 33.3% were DQw3.2 and 66.6% were DQw3.1. Haplotype analysis showed that DR4-DQw3.2 was in strong linkage with the U fragment (2.1 kb Taq I) of DQA2 (DX alpha) and with the L fragment (5.4 kb BamH I) of DOB. This study confirms previous observations of DQB polymorphisms in heterozygous IDDM patients, supports the protective effect of DQw3.1 (DQw7) against the development of the disease and demonstrates the importance of DQw3.2 (DQw8) for susceptibility to Type I diabetes.
 ...
PMID:Restriction fragment length polymorphism analysis of HLA haplotypes in families with type I diabetes mellitus. 196 92

The DQw3.2 specificity has previously been recognized using genomic RFLP analysis and certain combinations of monoclonal antibodies. Here we report three CD4+ T lymphocyte clones (TLCs) generated from a DR3,4; DQw2,w3.1 responder stimulated with cells from a DR3,4; DQw2,w3.2 donor, and using a modified cloning procedure involving enrichment of IL-2 receptor-positive T cell during priming. The resulting TLCs were strongly inhibited by some monoclonal anti-DQ, but not anti-DR or -DP antibodies. In panel studies using HLA homozygous stimulating cells, it was found that the TLCs recognize an HLA epitope encoded by a DQ gene carried only by DR4,DQw3.2 haplotypes. By comparison with published DQ chain amino acid sequences of some stimulating cells able or not to induce a response in these clones, evidence was obtained that Ala at position 57 on the DQ beta chain is most probably involved in the epitope. The epitope is present on cells from 12 out of 12 DR4,DQw3 insulin dependent diabetes mellitus (IDDM) patients, but on cells only from 6 out of 12 healthy DR4,DQw3 controls. Thus, a DQ-encoded epitope involving residue 57 on the DQ beta chain, and which is strongly associated to IDDM, may be recognized by T cells.
 ...
PMID:T lymphocyte clones recognizing an HLA-DQw3.2-associated epitope involving residue 57 on the DQ beta chain. 245 88

We have investigated restriction fragment length polymorphism (RFLP) of HLA and non-HLA regions of the genome in the homogeneous Danish population. Insulin-dependent diabetes mellitus (IDDM) patients and healthy individuals were selected for being HLA-DR 3/4 heterozygous to evaluate the influence of genes other than DR on disease susceptibility. Five different probes were used: HLA alpha and beta DQ (chromosome 6), the Ins 310 genomic fragment which detects a polymorphic region 5' to the insulin gene (chromosome 11), and cDNA for the constant regions of the T cell receptor alpha and beta genes (chromosomes 14 and 7). Fifteen cells homozygous for the HLA-D region were used to obtain reference DNA patterns. This allowed us to describe four splits among the HLA-DQw3 haplotypes (DQw3.1 to DQw3.4). The two new haplotypes DQw3.3 and DQw3.4 do not code for the TA10 serological marker which is found on DQw3.1 positive cells. One-hundred per cent of IDDM patients were typed as DQw3.2 versus 68 per cent for controls (p = 0.003). However, our results do not indicate a role for the Ins 310 or for the alpha DX locus region in IDDM susceptibility, in contrast to previous reports by others. The restriction enzymes that we have used did not reveal significant differences between DNA patterns of patients and controls with probes for the constant region of the T cell receptor genes.
 ...
PMID:Restriction fragment length polymorphism of HLA and non-HLA genes in DR3/4 heterozygous Danish insulin-dependent diabetic patients and healthy individuals: reassessment of the influence of alpha DX and insulin-linked polymorphic loci, and new splits of DQw3 haplotypes. 256 78

Almost all human leukocyte antigen (HLA) haplotypes positive for HLA-DR4 also carry the DQw3 specificity, which appears in one of two allelic forms, DQw3.1 or DQw3.2. Previous studies have shown that the frequency of the HLA DR4-DQw3.2 allele is approximately 95% among DR4-positive haplotypes of insulin-dependent diabetics (IDDM), but only 70% in DR4-positive haplotypes of unaffected individuals. Because this difference could be due to ethnic heterogeneity, it is important to establish whether the frequency of the DQw3.2 allele is also increased when haplotypes of diabetics are compared to those of "matched" unaffected individuals, as can be done within families. We have used the Genetic Analysis Workshop 5 (GAW5) data for this purpose. In every family, each parental DR4-bearing haplotype was categorized as "IDDM" if it appeared in any affected parent or offspring, or as "control" if not. When this was done, the frequencies of the DQw3.2 and 3.1 allele in 80 IDDM haplotypes were 94% and 6% respectively but 67% and 33% in 15 control haplotypes. This difference between the two kinds of haplotypes is highly significant (P less than 0.005).
 ...
PMID:HLA DR4-DQw3.1 and 3.2 haplotypes among insulin-dependent diabetics and their unaffected sibs in the GAW5 data. 256 53

Genetic studies indicate that the IDDM susceptibility genes in the HLA region are closely linked to the DR3 and DR4 specificities; however, these specificities do not define the actual susceptibility genes. Molecular studies confirm this hypothesis by demonstrating restriction fragment length polymorphism between DNA's of identical DR specificities and thereby separating the DR haplotypes into those strongly or weakly associated with IDDM. Further studies at the nucleotide sequence level demonstrate further heterogeneity, with DR4 being associated with at least three different DQ beta genes and five different genes of the DR beta-1 locus. However, the majority of these subtypes are now recognized either serologically or by T-cell responses in mixed lymphocyte cultures. Furthermore, the sequences associated with IDDM are those most commonly found in DR4 individuals, ie, Dw4 and DQw3.2. Clearly, these and other class II genes must be studied for additional DNA polymorphism and their relevance for IDDM. For example, the DX alpha, 2.1-kb Taql polymorphism shows a stronger correlation with IDDM than DR3. However, it is not even known if the DX alpha genes are expressed. In addition, little is known of the DQ beta and DR beta genes associated with different DR3-associated haplotypes. Furthermore, an IDDM susceptibility gene may contain important differences in flanking or intron sequences controlling expression of these genes. The methods of recombinant DNA technology are enabling these unanswered questions to be addressed.
 ...
PMID:Molecular biology of the HLA system in insulin-dependent diabetes mellitus. 330 Dec 40