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)

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

IgA nephropathy (IgAN) has been associated with HLA-DR4. We have recently described two non-allelic Taq I DQ beta gene-associated fragments sized 2.0 kb (T2) and 6.0 kb (T6), which strongly associate with DR4. T2 represents a polymorphism of the DQ beta gene and has been redesignated DQw8 (10th International HLA Workshop). The origin of the T6 fragment has not been determined, but probably represents a polymorphism of either the DQ beta or DX beta gene. When present together T2 and T6 define a subgroup of DR4 subjects at high risk of developing autoimmune disease. We have, therefore, studied DQ beta gene polymorphisms in IgAN. The DR antigen distribution was similar in IgAN and normal controls. The T2+/T6+ phenotype was present in 49% patients with IgAN compared to 15% of controls [P less than 0.0001, chi 2 = 32.8, Cramer's V = 0.41; relative risk = 5.5 (range, 2.8-11.0)]. Seventy-two percent of DR4+ IgAN patients and 29% of DR4+ controls were T2+/T6+ (P = 0.007, chi 2 = 17.0). These findings confirm the hypothesis that disease susceptibility genes are important in IgAN, and suggest that the putative gene(s) are located within or near to the DQ subregion. Moreover, similar DQ beta gene associations have been found in IDDM and pemphigus vulgaris, pointing to a common immunogenetic mechanism predisposing to several autoimmune diseases.
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PMID:HLA DQ region gene polymorphism associated with primary IgA nephropathy. 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

DNA restriction fragment length polymorphism (RFLP) typing of HLA-DR and DQ alleles of 60 Japanese type 1 (insulin dependent) diabetic patients and 115 controls was performed. RFLP typing of DRB1 showed increased frequency of DR9 and decreased frequencies of DR2 and DRW6 among patients compared to controls. In the RFLP typing of BamHI-digested DNA to DQ beta probe (BamHI-DQB1), the incidence of the 10.26 kb fragment, which represents either DQW4, DQW8 or DQW9, was markedly elevated in the patients, whereas the incidence of DQW6 was reduced. The predicted DR-DQ haplotype study revealed that DR4-DQW4 or DQW8, DRW8-DQW4 or DQW8 and DR9-DQW9 may contribute to susceptibility to type 1 diabetes. When serological typing of the 13 DRW8 patients was performed, all the 11 DRW8 patients carrying DQW4 or DQW8 (BamHI-10.26 kb) were positive for DQW3. These results indicated that the HLA-DQ locus may play an important role in the development of type 1 diabetes in the Japanese as well as other ethnic groups and that the DRW8-DQW8 haplotype may predispose to the disease in Japan.
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PMID:HLA class II (DR, DQ) in Japanese patients with type 1 diabetes mellitus. 198 37

Haplotypes including HLA A, B, C, DR, and DQ were compared in a study population comprising 18 Tunisian multiplex families with diabetic children. Eighty haplotypes found in IDDM patients were compared with 148 haplotypes present in healthy family members. RFLP analysis showed that two DR subtypes were significantly more common in the diabetic haplotypes (DR4-DQw8: 82 per cent in IDDM members compared to 0 per cent in healthy members, p less than 0.001 and DR-Dw25: 56 per cent in IDDM patients compared to 16.7 per cent in healthy members, p less than 0.001) and these were in most cases found in haplotype combinations with HLA A2 B44 DR4 DRw53 and HLA A 24 B18 DR3 genes, respectively.
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PMID:Extended HLA haplotypes in multiplex families with insulin dependent diabetes mellitus in Tunisian population: HLA serological typing and RFLP analysis. 198 95

In order to study the capacity of the first phase insulin response (FPIR) for predicting insulin-dependent diabetes (IDDM), we have performed one or more intravenous glucose tolerance tests (IVGTT) and determined islet-cell antibodies (ICA) and HLA-types in 220 first degree relatives of IDDM patients (194 siblings, 26 offsprings) aged 2 to 29 years. They were prospectively followed for periods ranging from 18 months to 8 years. The immunological and metabolic changes in 9 subjects who have developed IDDM or impaired glucose tolerance during the study and in 3 ICA-positive non-diabetic subjects were compared to those in ICA-negative subjects. Although the mean FPIR (1 + 3 min. plasma insulin) was significantly lower in ICA-positive compared with ICA-negative subjects, a unique low FPIR had no predictive value at the individual level. At repeated tests, the two groups followed distinctive evolutive patterns: ICA-negative subjects usually had higher FPIRs at a 2nd test, while FPIRs remained low or still decreased in ICA-positive subjects. Follow-up of subjects at high risk showed good concordance between the different predictive factors: among the 9 subjects who have developed IDDM, 7 had persisting ICA, 8 were HLA-DR3, DR4; the FPIR was consistently low in 3 and low at least once in 4. Progressive loss of the FPIR allowing to predict the time of onset of IDDM, was not observed.
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PMID:[Decrease of early insulin secretion, risk factor of insulin-dependent diabetes. Prospective study in families with diabetic children]. 201 14

First-degree relatives of patients with insulin-dependent (type I) diabetes (n = 264 from 106 families) were evaluated with HLA typing and determination of competitive insulin autoantibodies (CIAAs) and islet cell autoantibodies (ICAs). The levels of CIAAs in 30 relatives exceeded our upper limit of normal (greater than or equal to 39 nU/ml), and 30 had high-titer ICAs (greater than or equal to 40 Juvenile Diabetes Foundation units [JDF U]). Eleven of the HLA-typed relatives developed diabetes during follow-up. Twenty-three percent (28 of 123) of the relatives with at least one HLA-DR4 allele were CIAA+ (CIAA greater than or equal to 39 nU/ml) versus 4% (6 of 141) among DR4- relatives (P less than 0.0001). Twenty-one of 22 of the highest CIAA values were all in the DR4+ group (DR4+ vs. DR4-, P = 0.003, Wilcoxon's rank-sum test). HLA-DR3 did not correlate with the level of CIAAs, and neither DR3 nor DR4 correlated with titer of ICAs measured in JDF U. We conclude that, in first-degree relatives of patients with type I diabetes, there is a striking association with HLA-DR4 in both the prevalence of relatives exceeding the normal CIAA range and in the level of CIAAs. These data suggest that a gene on HLA-DR4 haplotypes contributes to the level of anti-insulin autoimmunity, and we hypothesize that DR4-associated diabetes susceptibility, distinct from DR3-associated susceptibility, may be secondary to this influence.
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PMID:Specific association of HLA-DR4 with increased prevalence and level of insulin autoantibodies in first-degree relatives of patients with type I diabetes. 204 Mar 87

Insulin-dependent diabetes mellitus (IDDM) susceptibility is associated with the DR4-DQw4 haplotype in Japanese and the DR4-DQw8/-Drw8-DQw4 genotype (among others) in whites. We investigated whether these Japanese and white individuals encode the same or a similar DQ alpha beta heterodimer, which may be an IDDM-susceptibility molecule in both populations. First, we carried out genomic DQA1 and DQB1 typing with sequence-specific oligonucleotide probes. The results revealed that Japanese DR4-DQw4 and white DR4-DQw8/DRw8-DQw4 IDDM patients carried the DQA1*0301 allele and the DQB1*0401 or DQB1*0402 allele, either in the cis (Japanese DR4-DQw4 individuals) or trans (white DR4-DQw8/DRw8-DQw4 individuals) position. Because the DQB1*0401 and DQB1*0402 alleles differ only at residue 23, these DQB1 genes are very similar. We next tested cells from these individuals with a particular DQ-specific T-lymphocyte clone, HH58. The clone was only restimulated with cells from Japanese individuals who carried the DQA1*0301 and DQB1*0401 alleles in the cis position or white individuals who carried the DQA1*0301 and DQB1*0402 alleles in the trans position. Thus, particular cis- or trans-encoded DQ alpha beta heterodimers, which in both cases are recognized by T lymphocytes, may confer susceptibility to IDDM in both ethnic groups.
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PMID:Particular HLA-DQ alpha beta heterodimer associated with IDDM susceptibility in both DR4-DQw4 Japanese and DR4-DQw8/DRw8-DQw4 whites. 204 Mar 92

1. The mode of inheritance of the DR3- and DR4-associated susceptibility genotype is essentially recessive, based on both the segregation data and the existence of Hardy-Weinberg equilibrium in Ashkenazi Jewish and possibly in patients of other populations. 2. Maternal effects may alter the expressivity of IDDM in some susceptible offspring, depending on the maternal DR genotype. Thus, the number of susceptible DR4 types inherited from the mothers may be decreased in certain population samples. Conceivably, these maternal effects also account for the smaller proportion of diabetic children born to diabetic women than to diabetic men. Conversely, maternal DRw6 may raise this risk. 3. The locus of the susceptibility gene is most likely in the DQ region. While specific DQA1 and DQB1 alleles are very closely associated with IDDM in some populations, neither is completely associated with it in DR4 haplotypes and neither accounts for the differences in IDDM susceptibility associated with DR3 haplotypes. 4. Linkage disequilibrium between DR and DP alleles in affected haplotypes indicates the existence of subsets of DR3 and DR7, which account for all or most of the risk to those haplotypes. The possibility of direct DP effects is less likely because the respective DP alleles are different and because DR4 does not maintain disequilibrium with DP alleles in either affected or unaffected haplotypes. 5. The DQA2-BglII-7.2Kb polymorphism in complete association with affected B8,DR3 haplotypes suggests the possible involvement of DQA2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HLA and IDDM: facts and speculations on the disease gene and its mode of inheritance. 204 89

It has now become clear that certain HLA antigens are associated with disease susceptibility more than any other genetic markers. Insulin-dependent diabetes mellitus (IDDM or type I) is an HLA-associated condition. Moreover, there is evidence to show that IDDM is a genetically programmed autoimmune disease. Studies of the HLA-DR region have shown a strong association with IDDM, with over 90 per cent of IDDM patients possessing DR3 and/or DR4. Although the HLA-DR region is a major component in the inherited disease susceptibility, it is not the only gene region involved. Recent studies demonstrated that HLA-DQ may be more closely linked to the disease locus than HLA-DR. Sequence analysis of the HLA-DQ3 gene products suggest that a single amino acid (aspartic acid) at position 57 is uniquely important for determining susceptibility or resistance to IDDM. Although there is a strong association of certain HLA loci with IDDM, it may not explain nor account for all the genetic susceptibility to the disease. It seems that 60 per cent of the genetic basis of IDDM is related to the HLA gene (chromosome 6) and another 40 per cent is non-HLA-associated (i.e., chromosomes 2, 7, 11, and 14). Even though great progress has been made in the understanding of the genetics of IDDM, the mode of inheritance of the disease remains controversial. The present review discusses various aspects of the autoimmune process believed to be involved in pancreatic beta cell destruction in individuals genetically susceptible to IDDM. The possible modes of inheritance and new data regarding estimated risks of transmitting the disease are presented.
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PMID:Insulin-dependent diabetes mellitus and immunogenetics: maternal and fetal considerations. 205 68


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