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 HLA-DQA1 and DQB1 genes have recently been recognized to be strong genetic markers of susceptibility to type 1 (insulin-dependent) diabetes mellitus. The Arg52 DQA1 and non-Asp57 DQB1 alleles of these genes correlate with the disease predisposition and the Asp57 DQB1 and non-Arg52 DQA1 alleles with disease protection. We investigated 113 patients with type 1 diabetes and 121 healthy subjects from the Russian population of Moscow using DNA amplification and dot-blot hybridization with sequence-specific oligonucleotides (SSO). Using conventional statistical methods we confirmed previous observations indicating the important role of the above-mentioned amino acid residues in susceptibility and resistance to type 1 diabetes. Relative risk values for all alleles and absolute risk for carriers of most predisposing allele combinations were calculated. The absolute risk for carriers of DQA1 and DQB1 gene alleles allowing for the formation of four possible 'diabetogenic' heterodimers on the surface of immunocompetent cells, regardless of the type of coding (cis or trans), was 2.54%, which is 13 times greater than the background risk for the Russian population--0.2% up to 30 years of age.
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PMID:Frequency analysis of HLA-DQA1 and HLA-DQB1 gene alleles and susceptibility to type 1 diabetes mellitus in Russian patients. 794 27

Susceptibility to insulin-dependent diabetes mellitus (IDDM) is determined by both genetic and environmental factors. The major genetic susceptibility to IDDM is conferred by genes in the HLA class II region on chromosome 6. In Caucasians, this susceptibility is thought to be determined by DQA1 and DQB1 genes including the presence of arginine at position 52 of the DQ alpha chain and the absence of aspartic acid at position 57 of the DQ beta chain. In Japanese subjects, IDDM has been found to be associated DR, DQA1, and DQB1 genes. Positive associations with arginine at position 52 of the DQ alpha chain have been demonstrated in Japanese IDDM patients. However, the majority of Japanese IDDM patients do not show positive association to the absence of aspartic acid at position 57 of the DQ beta chain. Susceptibility to IDDM in Japanese subjects appears to be due to combination of DR genes and DQA1-DQB1 haplotypes.
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PMID:[Analysis of HLA-DR, -DQA1, -DQB1 genes in Japanese IDDM patients]. 798 9

Using a highly discriminatory DNA typing technique, based on the polymerase chain reaction and reverse dot blot hybridization, more refined results were obtained on the association of particular HLA class II alleles, haplotypes and genotypes with insulin-dependent diabetes mellitus in the Belgian population. The previously reported predisposing effect for the DRB1*0301 encoded DR3 serologic specificity was confirmed and could be assigned to the DRB3*0200 encoded DR52b serologic specificity. A second high risk haplotype, DRB1*0401-DQB1*0302 encoding the DR4-DQ8 serologic specificity, accounted for increased susceptibility both in the total insulin-dependent diabetic population and among DR4-positive patients. Moreover, we found that these DR4 associated DRB1 and DQB1 alleles act as independent risk factors. A possible role for the DPB1 locus can be rejected since the observed predisposing effect for DPB1*0202 probably occurred due to linkage disequilibrium of this allele with DRB1*0301. Particular extended haplotypes accounted for the decreased relative risk observed for the DR2, DR11 and DR13 serologic specificities. The highest relative risk was observed for those DQA1/DQB1 genotypes, allowing for the formation of 4SS (DQ alpha Arg52+/DQ beta Asp57-) heterodimers.
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PMID:Association of particular HLA class II alleles, haplotypes and genotypes with susceptibility to IDDM in the Belgian population. 798 83

We examined the prevalence of HLA-DRB1, DQB1, DQA1 and TAP2 genes in children with insulin-dependent diabetes mellitus (type 1 diabetes). These HLA and TAP2 alleles were identified by dot-blot analysis of polymerase chain reaction (PCR)-amplified genomic DNA with sequence-specific oligonucleotide probes. The results show that those DQB1 alleles, which carry non-aspartic acid at position 57, in conjunction with DQA1 alleles carrying arginine at position 52, are strongly associated with susceptibility to type 1 diabetes. The prevalence of the TAP2* 0201 allele in diabetic patients was significantly lower than that in normal controls. Analysis of the data suggests that DQ alleles have the primary association with type 1 diabetes and that the association of TAP2 alleles with the disease is secondary.
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PMID:HLA-DQ and TAP2 genes in patients with insulin-dependent diabetes mellitus. 800 38

The transporter associated with antigen processing (TAP) encoded in the major histocompatibility complex (MHC) class II region is a molecule required for endogenous antigen processing. We have typed TAP polymorphism in 95 Japanese patients with insulin-dependent diabetes mellitus (DDM) and 75 normal controls. Amino acid substitutions at positions 333 and 637 of TAP1 and at positions 379, 665, and 687 of TAP2 were typed by the polymerase chain reaction (PCR)-sequence-specific oligonucleotide method. In addition, DNA typing of human leukocyte antigen (HLA)-DQA1 and -DQB1 loci was performed by the PCR-restriction fragment length polymorphism method. There was no significant difference between IDDM patients and normal controls in the frequencies of TAP1 and TAP2 alleles. On the contrary, the HLA-DQ locus showed a strong association with IDDM in the same series of subjects. The frequencies of HLA-DQA1*0301 and -DQB1*0401 were increased significantly and those of HLA-DQA1*0103, -DQB1*0501, -DQB1*0601 and -DQB1*0602 were decreased significantly in Japanese IDDM patients compared with normal controls. Positive linkage disequilibrium was observed between HLA-DQB1*0303 and TAP2C and between HLA-DQB1*0401 and TAP2B. Negative linkage disequilibrium was observed between HLA-DQA1*0103 and TAP2A. Even when subjects with HLA-DQA1*0103, -DQA1*0301, -DQB1*0302, -DQB1*0303, and -DQB1*0401 were considered separately, no significant differences was found in the distribution of TAP1 and TAP2 alleles between IDDM patients and normal controls. We conclude that it is not TAP but HLA-DQ that exhibits a primary association with Japanese IDDM.
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PMID:Lack of association of the transporter associated with antigen processing with Japanese insulin-dependent diabetes mellitus. 805 40

We examined HLA Class II antigens in 116 Japanese IDDM patients [84 typical IDDM (T-IDD); 32 slowly progressive IDDM (S-IDD)] by the hybridization protection assay (HPA) which is a novel HLA typing method based on hybridization of acridinium-ester-labeled DNA probes to amplified DNA. We detected HLA-DRB1, -DQA1 and -DQB1 genes by this method which is capable of analyzing over 50 samples within 4 h with high sensitivity. Positive associations were found in DRB1*0405, DRB1*0802, DRB1*0901, DQA1*0301, DQB1*0303 and DQB1*0401, negative correlations in DRB1*0403, DR2, DR12, DRB1*0801 or 03, DQA1*0101 or 02, DQA1*0501, DQB1*0301 and DQB1*0602 alleles. The absence of aspartic acid (Asp) at position 57 of the DRB1 chain and the presence of arginine (Arg) at position 52 of the DQA1 chain correlated positively with both types of IDDM. There were no significant differences in HLA between T-IDD and S-IDD. These results suggest that the absence of Asp at position 57 of the DRB1 chain and the presence of Arg at position 52 of the DQA1 chain are significant Japanese IDDM patients and that DRB1*0802, in which the amino acid at position 57 is aspartic acid, may play a role in the pathogenesis of IDDM. Also, T-IDD and S-IDD have common bases in the HLA gene.
Diabetes Res Clin Pract 1994 Mar
PMID:Analysis of MHC class II antigens in Japanese IDDM by a novel HLA-typing method, hybridization protection assay. 807 Mar 5

Levels of insulin autoantibodies (IAA) vary among different first degree relatives of insulin-dependent diabetes mellitus patients, suggesting genetic regulation. We previously reported elevated IAA among DR4-positive at risk relatives. In this study, 72/82 at risk relatives were IAA positive, of whom 75% (54/72) carried DR4 versus 20% (2/10) of IAA-negative relatives (P = 0.0004). However, 69% (18/26) of DR4-negative relatives were IAA positive. Since DR4 did not account for all IAA positivity, we analyzed DQA1 and DQB1 alleles. Homozygosity for DQA1 alleles deriving from the evolutionary lineage 4 (*0401, *0501, *0601) was associated with low IAA levels, while lineage 1-3 alleles (*0101, *0102, *0103, *0201, *0301) correlated with higher levels. Most (93%, 65/70) relatives with lineage 1-3 alleles were IAA positive (mean = 360 +/- 63 SEM nU/ml). Only 7/12 relatives homozygous for lineage 4 alleles were IAA-positive, with lower levels than relatives with lineage 1-3 alleles (mean = 55 +/- 15 SEM nU/ml, P < 0.0001; 7/12 vs 65/70, P = 0.004). The amino acid sequences of lineage 1-3 alleles uniquely share glutamic acid (E) and phenylalanine (F) at positions 40 and 51 (EF alleles). Lineage 4 alleles have glycine (G) and leucine (L) at those positions (GL alleles). 90% (65/72) of IAA-positive relatives had an EF allele, while only 75% (54/72) had DR4 (P = 0.01). Homozygosity for GL alleles (often DQA1 *0501 on DR3 haplotypes) correlated with little or no humoral response to insulin. Thus, HLA-DQB1 GL alleles, or other genes on haplotypes (e.g., DR3) that carry these DQA1 alleles, may confer recessive low responsiveness to insulin.
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PMID:Two subsets of HLA-DQA1 alleles mark phenotypic variation in levels of insulin autoantibodies in first degree relatives at risk for insulin-dependent diabetes. 820 Sep 80

In the last few years the improvement of our knowledge of the pathogenesis of type I diabetes mellitus has been possible mainly because of the development of studies of the role played by genetic factors and the better definition of lesion mechanisms. The availability of experimental models such as "non obese diabetic (NOD)" mice and "Bio-Breeding (BB)" rats, which develop a form of type I diabetes similar to that of humans, has provided many data regarding the relevance of T lymphocytes in the pathogenesis of the disease, and made it possible to anticipate the immunopathological steps leading to pre-insulitis, insulitis and, finally, to pancreatic beta-cell destruction. The analysis of sera of patients with type I diabetes has demonstrated the presence, also in the preclinical states, of several autoantibodies directed against specific autoantigenic structures of beta cells, which have come to be useful for early diagnosis and in the monitoring of the disease. However, hard evidence for a relevant role of these autoantibodies in the pathogenesis of the disease does not exist. At present, we can affirm that the expansion of autoreactive T lymphocytes specific for membrane antigens of beta cells is the most relevant immunological event for the induction and sustenance of insular lesions. Autoreactive T lymphocytes may be able to activate several effector systems of lesions through the production of multiple combinations of cytokines. The aetiology of the disease is certainly multifactorial and involves both genetic and environmental factors. With respect to the former, the most accurate studies have been performed on the HLA system. It has been clearly shown that type I diabetic patients more frequently display HLA DR3 and DR4 specificities. The results obtained by the application of molecular techniques have suggested considering as risk factors the occurrence of DQB1 0302 DQB1 0201 alleles, the presence of a neutral amino acid residue in position 57 of the DQ beta chain instead of aspartic acid, as well as an arginine residue in position 52 of the DQ alpha chain. With regard to acquired aetiological factors, the hypothesis that primary lesions of pancreatic islets could be due to some viral infections capable of triggering, through several undefined mechanisms, persistent and self-sustaining autoimmune reactions, has gained some credit.
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PMID:[Current views on the etiopathogenesis of type-I diabetes mellitus]. 821 79

Molecular genetics has had a substantial impact on our understanding of inherited susceptibility to insulin-dependent diabetes mellitus. Alleles at the HLA-DQA1 and DQB1 loci appear to have the greatest influence on diabetogenesis. Other promising loci are present on chromosome 11 in the vicinity of the insulin gene. We have sought not only to improve our prediction of insulin-dependent diabetes mellitus but also to reveal the underlying immune and nonimmune defects that predispose to autoimmune beta-cell destruction. Continued advances in the field of genetics will aid in the prevention of insulin-dependent diabetes mellitus, which is our ultimate goal.
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PMID:The genetics of autoimmune diabetes. Approaching a solution to the problem. 824 45

Demographic and biological data were collected from all Caucasian Type 1 diabetic patients (n = 279) who were recruited at clinical onset by the Belgian Diabetes Registry over 34 months. The male/female ratio was significantly higher for onset between age 20 and 40 years (2.4) than before age 20 years (1.0); no age-or sex-differences were noticed in serum fructosamine concentration. Total and high concentrations of insulin autoantibodies and islet cell antibodies were preferentially associated with the HLA DQA1*0301-DQB1*0302 susceptibility haplotype. The occurrence of both types of antibodies was also correlated, irrespective of haplotype. At onset before age 10 years, the high risk genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 was more prevalent than all other DQA1-DQB1 genotypes taken together, leading to a higher prevalence of the DQA1*0301-DQB1*0302 haplotype in this age group (75%) than in the 10-39 years age group (54%). Under age 10 years, the presence of DQA1*0301-DQB1*0302 was strongly associated with insulin autoantibodies (90%) and islet cell autoantibodies (92% with 85% of high titre), whereas patients without this haplotype were less frequently positive for insulin autoantibodies (31%) or islet cell autoantibodies (38% high titre). In the group with onset at age 10-39 years, the DQA1*0301-DQB1*0302 haplotype presented a lower association with insulin autoantibodies (approximately 40%) and islet cell autoantibodies (50 to 65% high titre), prevalences which no longer differed from those in subjects lacking this haplotype.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with the HLA DQA1*0301-DQB1*0302 haplotype at clinical type 1 (insulin-dependent) diabetes mellitus before age 10 years, but not at onset between age 10 and 40 years. The Belgian Diabetes Registry. 827 Jan 30


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