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)

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.
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PMID:Use of the polymerase chain reaction mismatch technique to identify the HLA-DQw8 allele in patients with insulin-dependent diabetes mellitus. 172 61

To assess a possible HLA association with anti-insulin autoantibodies (IAAs) in human insulin-dependent (type I) diabetes, 51 newly diagnosed type I diabetic patients (mean age 22 +/- 8 yr) were typed for HLA-DR and HLA-DQ and studied for IAAs before exogenous insulin therapy with a competitive radioimmunoassay (normal range less than or equal to 49 nU/ml). The level of IAAs in 16 patients exceeded our upper limit of normal, and 18 had high-titer islet cell antibodies (ICAs; greater than or equal to 40 Juvenile Diabetes Foundation U). A striking association with HLA-DR4 (DQw3) in both the prevalence and the level of IAAs was found (IAA positivity in patients with DR4/4 vs. DR4 heterozygous vs. non-DR4: 90 vs. 29%, corrected [c] P less than 0.01, vs. 5%, Pc less than 0.0001; IAA positivity in patients with DR4 vs. non-DR4: 50 vs. 5%, Pc less than 0.005; IAA level in patients with DR4/4 vs. DR4 heterozygous vs. non-DR4: 111 vs. 17 nU/ml, Pc less than 0.01, vs. 20 nU/ml, Pc less than 0.0001; IAA level in patients with DR4 vs. non-DR4: 45 vs. 20 nU/ml, Pc less than 0.01). In contrast, none of the DR3+ subjects had IAAs above normal range, except in conjunction with DR4 (DR3 vs. non-DR3: 12 vs. 42%, Pc less than 0.05). However, there was no significant relationship between DR3 and IAAs after correcting for the number of DR4 alleles. No relationship was seen between age of onset, IAA level, and HLA typing in our population, and no relationship was found between ICA positivity and HLA antigens.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HLA-associated insulin autoantibody formation in newly diagnosed type I diabetic patients. 193 22

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.
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PMID:Restriction fragment length polymorphism analysis of HLA haplotypes in families with type I diabetes mellitus. 196 92

New immunogenetic markers are demonstrated for type 1 diabetes mellitus, Graves' disease and Hashimoto's thyroiditis. These markers are detected by restriction fragment length polymorphism (RFLP) analysis of HLA-D region genes and genes for the tumor necrosis factor alpha (TNF alpha). By analysing haplotypes transmitted to diabetic probands in families and comparing them with haplotypes that are only transmitted to healthy siblings it is shown that DQw8-DQB1 gene variation is important for susceptibility on DR4 haplotypes. Analysis of this DQw3 split in patients with Hashimoto's thyroiditis reveals that the other DQB1 gene variation, namely DQw7, displays the strongest association with Hashimoto's thyroiditis. This DQB1 variation has several implications for susceptibility and/or pathogenesis of both autoimmune endocrine diseases. Novel polymorphisms for TNF alpha are detected and it is shown that heterozygosity for TNF polymorphisms is significantly associated with type I diabetes and Graves' disease. Furthermore, DR4 haplotypes transmitted to diabetic probands possess significantly more the 10.5 Kb fragment in contrast to DR4 haplotypes transmitted only to healthy family members. This genetic polymorphism raises functional issues in susceptibility to autoimmune disease and can lead to a new explanation of the enigmatic HLA-association with a variety of diseases.
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PMID:Immunogenetic markers for autoimmune diseases of the endocrine system. 197 65

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.
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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.
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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).
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PMID:HLA DR4-DQw3.1 and 3.2 haplotypes among insulin-dependent diabetics and their unaffected sibs in the GAW5 data. 256 53

HLA class II genes have been implicated in susceptibility to a number of diseases. We have previously identified two allelic variants of DQw3 and have shown that DR4-DQ beta 3.2 haplotypes are associated with increased risk of IDDM whereas DR4-DQ beta 3.1 haplotypes are not. DR5 and DR8 DQw3+ individuals are exclusively DQ beta 3.1 and share numerous restriction sites within the DQ beta genes with DR4-DQ beta 3.1 individuals. In order to compare the DQ beta 3.1 genes associated with different haplotypes, we have sequenced coding and noncoding regions of the DQ beta genes from a DR4-DQ beta 3.1 HTC (ER) and a DR8-DQ beta 3.1 HTC (LUY). LUY and ER DQ beta genes share nucleotide substitutions in both the beta 1 and beta 2 exons, yielding six amino acid replacements distinguishing them from DQ beta 3.2. In the noncoding regions as well, LUY and ER share nucleotide substitutions distinguishing their DQ beta 3.1 genes from DQ beta 3.2. These data support the concept that the DQ beta 3.1 allele was introduced onto different backgrounds via homologous recombination.
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PMID:Molecular analysis of DQ beta 3.1 genes. 289 47

HLA-DR4, Dw4-associated haplotypes associated with IDDM and JRA were compared using genomic DNA restriction fragment analysis to distinguish among DQ beta and alpha alleles linked to DR4. DQ beta polymorphisms that subdivide the HLA-DQw3 specificity into DQ3.1 and 3.2 alleles were identified. More than 90% of DR4+ IDDM patients express one of these alleles, DQ3.2; restriction enzyme mapping indicates that the presence of this allele also accounts for the genomic fragment patterns previously reported in IDDM. Furthermore, haplo-identical siblings of DQ3.2 IDDM patients also carry the DQ3.2 allele, regardless of clinical presentation. In contrast, DR4+ JRA patients show no allelic preference at DQ beta, implicating different HLA genetic contributions in these two DR4-associated diseases.
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PMID:Specific genomic markers for the HLA-DQ subregion discriminate between DR4+ insulin-dependent diabetes mellitus and DR4+ seropositive juvenile rheumatoid arthritis. 301 39

We have investigated DNA polymorphism of the class II alpha chain genes in HLA typed patients with insulin dependent diabetes mellitus (IDDM; n = 79), celiac disease (CD; n = 46), dermatitis herpetiformis (DH; n = 53), and controls (n = 86). Preferential allelic associations of HLA genes and gene products have thus been constructed for susceptibility to these diseases. DR alpha and DQ alpha gene polymorphisms indicated heterogeneity of HLA DR3, DRw6, and DR7, and HLA DR2 and DRw6, respectively. In DR7 positive CD patients a 3.8-kilobase (kb) DR alpha fragment, which correlated with DQw3, was found in only 11% of patients compared with 45% of corresponding controls (P less than 0.05). An increased frequency of a DX alpha genotype UU in all three diseases was found (IDDM 59%, DH 45%, CD 48%, compared to 21% in controls, P less than 0.001), which is not explained solely by the increased frequencies of DR3-DX alpha U. We therefore conclude part of the genetic susceptibility for these three conditions is encoded by genes within the DQ-DX subregion.
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PMID:HLA class II alpha chain gene polymorphisms in patients with insulin-dependent diabetes mellitus, dermatitis herpetiformis, and celiac disease. 380 83


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