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)

IDDM patients of North East Italian region were molecularly typed for their HLA-DQB1 and DQA1 loci by using allele specific oligonucleotide probes and PCR amplified genomic DNA. IDDM status strongly correlated with DQB1 alleles carrying a non-aspartic acid residue in position 57 of DQ beta chain and DQA1 alleles with an arginine residue in position 52 of DQ alpha chain. Genotype analysis revealed that individuals with two DQB1 alleles having a non-aspartic residue in position 57 and two DQA1 alleles with an arginine residue in position 52 had the highest relative risk of disease: they constituted 41% of IDDM patients as compared to 0% of controls. Heterozygosity either at residue 57 of DQB1 or residue 52 of DQA1 was sufficient to abrogate statistical significance for disease association, although 43.6% of IDDM patients were included in these two groups as compared to 21.6% of normal controls. On the other hand the presence of two DQB1 alleles with aspartic acid in position 57 was sufficient to confer resistance to disease irrespective of the DQA1 genotype. Based on the number of possible susceptible heterodimers an individual can form, it was found that 85% of IDDM cases could form two or more heterodimers (two in cis and two in trans), but no IDDM case was found to form one susceptible heterodimer in cis. These results demonstrate that the complete HLA-DQ genotype, more than single DQB1 or DQA1 alleles or DQB1-DQA1 haplotypes, is associated with the highest risk of disease. Screening of the population for preventive purposes and/or early signs of IDDM should then take advantage of this result and "susceptible homozygous" individuals should be followed very closely and considered the first group of choice for possible new therapeutical trials.
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PMID:The complex interplay of the DQB1 and DQA1 loci in the generation of the susceptible and protective phenotype for insulin-dependent diabetes mellitus. 818 82

Serological typing of HLA-DR antigens was performed on 116 patients with IDDM and 380 healthy controls. As expected a high incidence of HLA-DR3 and DR4 antigens was observed in patients with IDDM. However, the HLA-DR2 antigen, which rarely occurs in IDDM and is considered to confer protection against IDDM, was found in equal distribution (35%) in both patients and controls. HLA-DQ genotype analysis in 10 children with IDDM and 13 controls, all with the HLA-DR2 haplotype, showed that the great majority of affected children and normal controls carry the DR2 (16) or AZH-DQA1 *0102, DQB *0502 subtype. The high incidence of this subtype in normal individuals possibly explains why the DR2 antigen does not offer protection against IDDM in Greeks.
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PMID:Genetic predisposition and IDDM in Greece. 826 24

To compare the quantitative effect of the DQ alpha beta heterodimers DQ alpha 52 Arg+, beta 57 Asp- and DQ alpha 1*0501, beta 1*0201 on susceptibility to IDDM and CD, we characterized, at the genomic level, the DQ alpha 52 and DQ beta 57 residues of 50 IDDM Italian patients observed in Rome. The results were compared with those of a previous study concerning the oligotyping of DQ dimers in a group of CD children belonging to the same population. Our data confirm that both diseases are primarily associated with HLA-DQ alpha beta heterodimers, but the distributions of the respective susceptible DQA1 and DQB1 alleles in the two diseases were different. In fact, the highest risk of IDDM is for subjects alpha SS, beta SS that could express, by either cis- or trans-association, four susceptible heterodimers and decreases in proportion to the number of these; in regard to CD, the highest risk was found for individuals who carried only one predisposing heterodimer.
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PMID:Different dose effect of HLA-DQ alpha beta heterodimers in insulin-dependent diabetes mellitus and celiac disease susceptibility. 832 Jan 34

The polymorphism of the LST-1 gene (the human homologue of the mouse B144 gene) can be identified by Pvu II restriction enzyme digestion. We investigated the contribution of this RFLP to disease susceptibility in 117 patients with type I diabetes mellitus (IDDM), 110 with Graves' disease (GD) and 93 healthy controls. The distribution of the different LST-1 alleles (LST-1*1:1323 bp, LST-1*2:610 bp/713) was similar among IDDM and GD patients as well as in controls. The combination of DQA1*0501, DQB1*0201 and DQB1*0301, all predisposing to endocrine autoimmune disease, with LST-1*1 or LST-1*2 was not increased in patients. Analysis of two informative families with IDDM demonstrated cosegregation of DQA1 and DQB1 alleles with LST-1 alleles. No association of LST-1 polymorphisms with IDDM nor GD could be demonstrated.
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PMID:PVU II polymorphism of LST-1 (leucocyte specific transcript-1) in type I diabetes mellitus, Graves' disease and healthy controls. 854 34

Insulin-dependent diabetes mellitus (IDDM) is strongly associated with particular HLA-DQ alpha/beta markers in white population. The heterodimers conformation composed of a DQ alpha chain with an arginine at residue 52 (Arg52) combined to a DQ beta chain lacking an aspartic acid at residue 57 (non Asp57) increase markedly the risk to develop IDDM. To confirm this association, 63 IDDM patients from Santiago de Chile registry, 20 IDDM patients from Temuco registry and 74 unrelated healthy non diabetic control subjects were studied. With polymerase chain reaction (PCR) and sequence specific oligonucleotide probes the individuals were typed for their HLA-DQA1 and DQB1 alleles, their DQA1/DQB1 genotype and heterodimers conformation were compared. In diabetic population both markers Arg52 homocygote and non Asp57 homocygote were markedly increased regard to control subjects (R/R: 0.76 and 0.85 vs 0.33; ND/ND: 0.78 and 0.75 vs 0.50, p < 0.05). A high relative risk (RR) was determined for both homocygote markers in IDDM groups. Arg52 DQ alpha (R)/non Asp57 DQ beta (ND) heterodimers were strongly associated with susceptibility to IDDM. A high RR was observed in patients with four susceptibility DQ heterodimers (RR1: 13.7 in IDDM-Santiago and RR2: 18.6 in IDDM-Temuco, p < 0.00003). The HLA-DQ alpha/beta markers and their risk heterodimers are increased in our diabetic population and could be considered as susceptibility markers to develop IDDM.
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PMID:[Genetic predisposition to develop insulin-dependent diabetes mellitus. A population study in Santiago and Temuco, Chile]. 873 11

HLA class II polymorphism in Moroccan IDDM patients has not been investigated so far. In this study, HLA-DRB1, -DQA1, and -DQB1 allele and haplotype frequencies were analyzed in 125 unrelated Moroccan IDDM patients and 93 unrelated healthy controls, all originating from the Souss region and mostly of Berber origin. Some common features with other Caucasian groups were observed, in particular, a predisposing effect of the DRB1*03-DQA1*0501-DQB1*0201 and DRB1*04-DQA1*0301-DQB1*0302 alleles or allelic combinations. The Moroccan IDDM group also presented with more specific characteristics. Among DRB1*04 subtypes, DRB1*0405 was associated with susceptibility to and DRB1*0406 with protection from the disease. The haplotype and the relative predispositional effect (RPE) analyses indicated that the DRB1*08-DQA1*0401-DQB1*0402 haplotype was also associated with susceptibility to IDDM. Interestingly, the DRB1*09-DQA1*0301-DQB1*0201 haplotype, completely absent from the control group and very rare in North African populations, was observed in 7.2% of the Moroccan diabetics. Conversely, the DRB1*07-DQA1*0201-DQB1*0201 and DRB1*15-DQA1*0102-DQB1*0602 haplotypes were associated with protection from IDDM. Finally, we observed an age-dependent genetic heterogeneity of IDDM, the frequencies of predisposing alleles being higher and those of protective alleles lower in childhood- than in adult-onset diabetics. Our data on Moroccan diabetics, together with data on European and Northern Mediterranean patients, suggest a gradient of various HLA class II predisposing and protective markers that link these populations.
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PMID:Distribution of HLA class II alleles and haplotypes in insulin-dependent Moroccan diabetics. 887 68

HLA-DQ genes are the main inherited factors predisposing to IDDM. This gene region harbors long terminal repeat (DQ LTR) elements of the human endogenous retrovirus HER V-K, which we analyzed for a possible association with disease. We first investigated whether LTR segregate with DQ alleles in families. Members (n = 110) of 29 families with at least one diabetic child, unrelated patients with IDDM (n = 159), and healthy controls (n = 173) were analyzed. Genomic DNA was amplified for DQ LTR3 by a nested primer approach as well as for DQA1 and DQB1 second exons, to assign DQA1 and DQB1 alleles. DQ LTR segregated in 24 families along with DQ alleles. Of the 29 families, 20 index patients were positive for DQ LTR. The DQ LTR was in all patients on the haplotype carrying the DQA1 *0301 and DQB1 *0302 alleles. A majority of patients had DQ LTR (62%) compared with controls (38%) (p < 1.3 x 10(-5)), even after matching for the high-risk alleles DQA1 *0501, DQB1 *0201-DQA1 *0301, and DQB1 *0302 (79% of patients and 48% of controls; p < 0.02). Subtyping for DRB1 *04 alleles in all DQB1 *0302+ individuals showed 56% DRB1 *0401, DQB1 *0302 [LTR' patients vs. 29% controls with the same haplotype (p < 0.002)]. In conclusion, these data demonstrate the segregation of DQ LTR with DQA1, DQB1 alleles on HLA haplotypes. Furthermore their presence on DRB1 *0401-, DQA1 *0301-, and DQB1 *0302-positive haplotypes suggest that they contribute to DQ-related susceptibility for IDDM.
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PMID:Endogenous retroviral long terminal repeats of the HLA-DQ region are associated with susceptibility to insulin-dependent diabetes mellitus. 889 33

MHC class II genes play an important role in the autoimmune destruction of the pancreatic b-cell occurring in IDDM. The genetic pattern of the disease was investigated in Mexican Mestizos. The serological findings of HLA antigens showed a significant association of DR3, DR4, DQ2 and DQ8 and a protective effect of DR11, DR15, DQ5, DQ6 and DQ7. With these results, DNA analysis of HLA-DRB1, B3, B4, DQA1, DQB1, DPA1, DPB1 genes was performed using PCR with allele specific oligotyping. Among the patients, 92.78 carry DQA1 alleles that have ARG in position 52 of DQa chain, and 78.2% are ASP- in DQ5-57. The RR for homozygotes is 32.8 and 5.6, respectively. The main haplotype involved is DRB1*0405, DQA1*0301, DQB1*0302. Thus, DQa and DQb form a relevant recognition site for the "diabetogenic peptidett which induces the autoimmune destruction. Positions 57 and 74 of DRB1 locus contribute highly to the expression and severity of IDDM in Mestizos and other ethnic groups, but not in Caucasians or Blacks.
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PMID:[MHC-dependent molecular mechanisms of susceptibility and protection in type I diabetes in Mexicans]. 894 98

Many studies have shown an association of IDDM with polymorphisms in the HLA region on chromosome 6p21. Previously our case-control study in the Belgian population showed significant association between IDDM and certain HLA class II alleles, in particular Lys71+, encoding DRB1 alleles. In the present study, 81 Danish multiplex IDDM families and 82 healthy Danish controls were examined for polymorphisms in the HLA-DRB genes and 54 of the 81 families for polymorphisms in HLA-B, -DQA1, -DQB1, -TNFA, and -TNFB genes. The results confirm our previous studies in the Belgian population and show that DRB1Lya71+/+ homozygotes have a relative risk (RR) of 103.5. Linkage between IDDM and DRB1 alleles that encode Lys71+ was shown by affected zib pair analysis which showed strong linkage (p < 1 x 10(-6). By family based association studies, the DRB1Lys71+ was identified as the allale which increased susceptibility to develop IDDM most in the HLA region (haplotype relative risk = 8.38). Haplotype analysis confirmed the increased risk contributed by DRB1Lys71+ alleles and in addition showed that DRB1Lys71- provides protection against IDDM even in the presence of DQB1Aep47-. These results indicate that DRB1Lys71+ screening is a powerful test compared to full HLA typing to determine the risk for a random person to develop IDDM in the Danish population, with an even higher probability than shown previously for the Belgians.
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PMID:Linkage and association of the HLA gene complex with IDDM in 81 Danish families: strong linkage between DR beta 1Lys71+ and IDDM. 895 Jun 68

The aim of this study was to compare the genetic susceptibility linked to the HLA Class II region genes of the Major Histocompatibility Complex in isolated insulin-dependent diabetes mellitus (1a-IDDM) and insulin-dependent diabetes mellitus associated with another autoimmune endocrinopathy (1b-IDDM). HLA genes DRB1, DQA1 and DQB1 were studied at the genomic level, as well as genes TAP1 and TAP2. One hundred and seventy-nine 1a-IDDM diabetic patients were compared with 83 1b-IDDM patients. While it appeared that common genetic traits characterize diabetes regardless of the subtype (1a or 1b), certain features differentiate the two forms of IDDM. Extending the analysis of risk haplotypes DRB1*03 and DRB1*04 to TAP genes elicited a difference between 1a-IDDM and 1b-IDDM patients. Haplo-type DRB1*03 was thus characterized in 1a-IDDM patients by a lower frequency of alleles TAP1-B (13.5%) and TAP2-B (16.2%), not found in 1b-IDDM patients (33.3% for each allele). Likewise, haplotype DRB1*04 is characterized in 1b-IDDM patients by a lower frequency of alleles TAP1-C (4.0%) and TAP2-B (8.0%) than in 1a-IDDM patients (22.2% and 25.9%, respectively). In total, this study showed that extending the characterization of HLA Class II haplotypes to TAP genes discriminates between the forms of diabetes restricted to a specific pancreatic affection and those reflecting a wider autoimmune disorder affecting several organs.
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PMID:Genetic heterogeneity between type 1a and type 1b insulin-dependent diabetes mellitus: HLA class II and TAP gene analysis. 898 36


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