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 incidence of type 1 diabetes in Korea is less than 1/10th of that in the United States, and it has been suggested that human leukocyte antigen (HLA) alleles of Asian patients associated with diabetes differ from those of Caucasians. In this study we analyzed the common susceptibility and transmission pattern of a series of HLA DRB1-DQB1 haplotypes to Korean and Caucasian patients with type 1 diabetes. We performed HLA DR and DQ typing of 158 type 1 diabetic patients in a case control study, 140 nondiabetic subjects from the same geographical area, 49 simplex families from Seoul, and 283 families from the Human Biological Data Interchange. Although the haplotype frequencies in the two populations are quite different, when identical haplotypes are compared, their odds ratios are nearly the same. For all parental haplotypes, the transmission to diabetic offspring was similar for Korean and Caucasian families (r = 0.8; P: < 10(-)(4)). Allowing for ethnic differences in allelic associations due to different frequencies of DRB1 and DQB1 haplotypes (linkage disequilibrium), these data show, not only by case-control comparison but also by transmission analyses of the haplotypes, that the susceptibility effects of DRB1-DQB1 haplotypes are consistent in Koreans and Caucasians. Thus, the influence of class II susceptibility and resistance alleles appears to transcend ethnic and geographic diversity of type 1 diabetes.
 ...
PMID:Common susceptibility and transmission pattern of human leukocyte antigen DRB1-DQB1 haplotypes to Korean and Caucasian patients with type 1 diabetes. 1113 5

We assessed the prevalence of families with both type 1 and type 2 diabetes in Finland; and we studied, in patients with type 2 diabetes, the association between a family history of type 1 diabetes, glutamic acid decarboxylase (GAD) antibodies (GADab), and type 1 diabetes-associated human leukocyte antigen (HLA) DQB1-genotypes. Further, in mixed type 1/type 2 diabetes families, we investigated whether sharing an HLA haplotype with a family member with type 1 diabetes influenced the manifestation of type 2 diabetes. Among 695 families ascertained through the presence of more than 1 patient with type 2 diabetes, 100 (14%) also had members with type 1 diabetes. Type 2 diabetic patients from the mixed families had, more often, GADab (18% vs. 8%, P < 0.0001) and DQB1*0302/X genotype (25% vs. 12%, P = 0.005) than patients from families with only type 2 diabetes; but they had a lower frequency of DQB1*02/0302 genotype, compared with adult-onset type 1 patients (4% vs. 27%, P < 0.0001). In the mixed families, the insulin response to oral glucose load was impaired in patients who had HLA class II risk haplotypes, either DR3(17)-DQA1*0501-DQB1*02 or DR4*0401/4-DQA1*0301-DQB1*0302, compared with patients without such haplotypes (P = 0.016). This finding was independent of the presence of GADab. We conclude that type 1 and type 2 diabetes cluster in the same families. A shared genetic background with a patient with type 1 diabetes predisposes type 2 diabetic patients both to autoantibody positivity and, irrespective of antibody positivity, to impaired insulin secretion. The findings support a possible genetic interaction between type 1 and type 2 diabetes mediated by the HLA locus.
 ...
PMID:Possible human leukocyte antigen-mediated genetic interaction between type 1 and type 2 Diabetes. 1115 11

The predisposition to develop a majority of autoimmune diseases is associated with specific genes within the human leukocyte antigen (HLA) complex. However, it is frequently difficult to determine which of the many genes of the HLA complex are directly involved in the disease process. The main reasons for these difficulties are the complexity of associations where several HLA complex genes might be involved, and the strong linkage disequilibrium that exists between the genes in this complex. The latter phenomenon leads to secondary disease associations, or what has been called 'hitchhiking polymorphisms'. Here, we give an overview of the complexity of HLA associations in autoimmune disease, focusing on type 1 diabetes and trying to answer the question: how many and which HLA genes are directly involved?
 ...
PMID:HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved? 1117 19

Type 1 diabetes (T1D; or insulin-dependent diabetes mellitus, IDDM) is an autoimmune disease with both genetic and environmental components. In addition to the human leukocyte antigen (HLA) complex, the single major genetic contributor of susceptibility, an unknown number of other unidentified genes are required to mediate disease. Although many loci conferring susceptibility to T1D have been mapped, their identification has proven problematic due to the complex nature of this disease. Our strategy for finding T1D susceptibility genes has been to test for human homologues of loci implicated in diabetes-prone NOD (non-obese diabetic) mice, together with application of biologically relevant stratification methods. We report here a new susceptibility locus, IDDM18, located near the interleukin-12 (IL-12)p40 gene, IL12B. Significant bias in transmission of IL12B alleles was observed in affected sibpairs and was confirmed in an independent cohort of simplex families. A single base change in the 3' UTR showed strong linkage disequilibrium with the T1D susceptibility locus. The IL12B 3' UTR alleles showed different levels of expression in cell lines. Variation in IL-12p40 production may influence T-cell responses crucial for either mediating or protecting against this and other autoimmune diseases.
 ...
PMID:Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. 1117 71

Specific and major histocompatibility complex (MHC)-restricted T-cell recognition of antigenic peptides is based on interactions of the T-cell receptor (TCR) with the MHC alpha helices and solvent exposed peptide residues termed TCR contacts. In the case of MHC class II-presented peptides, the latter are located in the positions p2/3, p5 and p7/8 between MHC anchor residues. For numerous epitopes, peptide substitution studies have identified the central residue p5 as primary TCR contact characterized by very low permissiveness for peptide substitution, while the more peripheral positions generally represent auxiliary TCR contacts. In structural studies of TCR/peptide/MHC complexes, this has been shown to be due to intimate contact between the TCR complementarity determining region (CDR) three loops and the central peptide residue. We asked whether this model also applied to two HLA-DR presented epitopes derived from an antigen targeted in type 1 diabetes. Large panels of epitope variants with mainly conservative single substitutions were tested for human leukocyte antigen (HLA) class II binding affinity and T cell stimulation. Both epitopes bind with high affinity to the presenting HLA-DR molecules. However, in striking contrast to the standard distribution of TCR contacts, recognition of the central p5 residue displayed high permissiveness even for non-conservative substitutions, while the more peripheral p2 and p8 TCR contacts showed very low permissiveness for substitution. This suggests that intimate TCR interaction with the central peptide residue is not always required for specific antigen recognition and can be compensated by interactions with positions normally acting as auxiliary contacts.
 ...
PMID:Structural analysis of two HLA-DR-presented autoantigenic epitopes: crucial role of peripheral but not central peptide residues for T-cell receptor recognition. 1125 3

Type 1 diabetes mellitus is a common disease with a complex mode of inheritance. Its aetiology is underpinned by a major locus, insulin-dependent diabetes mellitus 1 (IDDM1) in the human leukocyte antigen (HLA) region of chromosome 6p21, and an unknown number of loci of lesser individual effect. In linkage analyses IDDM1 is a single peak, but it is evident that the linkage is caused by allelic variation of three adjacent genes in a 75 kb region, namely the class II genes, HLA-DRB1, -DQA1 and -DQB1. However, even these three genes may not explain all of the HLA association. We investigated, in the founder population of Sardinia, whether non-DQ/DR polymorphic markers within a 9.452 Mb region encompassing the whole HLA complex further influence the disease risk, after taking into account linkage disequilibrium with the disease loci HLA-DQB1, -DQA1 and -DRB1. We generalized the conditional association test, the haplotype method, to detect marker associations that are independent of the main DR/DQ disease associations. Three regions were identified as risk modifiers. These associations were not only independent of the polymorphic exon 2 sequences of HLA-DQB1, -DQA1 and -DRB1, but also independent of each other. The individual contributions of these risk modifiers were relatively modest but their combined impact was highly significant. Together, alleles of single nucleotide polymorphisms at the DMB and DOB genes, and the microsatellite locus TNFc, identified approximately 40% of Sardinian DR3 haplotypes as non-predisposing. This conditional analysis approach can be applied to any chromosome region involved in the predisposition to complex traits.
 ...
PMID:Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci. 1128 54

The human leukocyte antigen (HLA) system plays a crucial role in the autoimmune process leading to childhood diabetes. The purpose of this study was to evaluate the association between type 1 diabetes and the polymorphism encoded by the HLA-DQB1 gene by using case-parents trios. The study area was the metropolitan region of Santiago, Chile, and cases were ascertained from March 1997 to August 1998. Genotyping was performed in 94 trios comprising incident cases less than 17 years of age at the time of diagnosis and their parents. The transmission/disequilibrium test was used to detect differential transmission in the HLA-DQB1 locus. The authors found that alleles DQB1(*)0302 and DQB1(*)0201 were strongly associated with the disease. By using 1:3 matched sets of cases-pseudosibs and conditional logistic regression models, allelic relative risks were estimated for DQB1(*)0302 (r = 7.2, 95% confidence interval: 2.8, 18.5) and DQB1(*)0201 (r = 4.7, 95% confidence interval: 1.9, 11.6); DQB1(*)0301 was considered the baseline allele. When case-parents trios were used, alleles DQB1(*)0302 and DQB1(*)0201 were strongly associated with a higher risk of type 1 diabetes in the population of SANTIAGO:
 ...
PMID:Association between HLA-DQB1 alleles and type 1 diabetes in a case-parents study conducted in Santiago, Chile. 1129 53

We established the detailed polymorphism of the 5'-flanking region and the first exon of the human leukocyte antigen (HLA)-DQB1 alleles. One hundred and forty-five Spanish rheumatoid arthritis (RA) patients and 200 healthy voluntary blood donors from southern Spain along with 42 B-cell lines were analyzed for the presence of the retrovirus-derived long terminal repeats (LTRs) LTR3, LTR5, and LTR13. LTR3 positivity was always associated with certain DQB1 alleles, i.e., *0302, *0402, *0601, *0202, and *0305. Sequencing analysis of the 5'-flanking region of DQB1*0301, *0303 and *0502 alleles in homozygous B-cell lines showed the absence of LTR3 and a massive deletion of 5635 base pairs. The undetected deletion in the flanking region of some DQB1 alleles and a lack of stratification for HLA typing explain previously reported associations of the LTR3 element with RA and type I diabetes (IDDM). LTR5 showed identical distribution to LTR3, consistent with a previously suggested LTR3-LTR5 tandem arrangement. LTR13 positivity was associated with DQB1*0302, *0303, and *0402 alleles. Distributions of the LTR elements in all B-cell lines, RA patients, and controls could be explained entirely by linkage disequilibrium with DQB1 alleles, independently of the haplotypes carrying them. LTR elements are known to regulate gene expression. Therefore, a possible involvement of LTR13 in the association of DQB1*0302, *0303, and *0402 with IDDM requires further investigation. The sequencing results of the DQB1 first exon demonstrated that DQB1*0601 was generated by a recombination event between a DR53 and a non-DR53 haplotype. Our results shed new light on the phylogeny of the HLA region and the possible contribution of DQB1 to susceptibility to autoimmunity.
 ...
PMID:Distribution of HERV-LTR elements in the 5'-flanking region of HLA-DQB1 and association with autoimmunity. 1134 87

Exposure of human pancreatic islets to a mixture of cytokines induces expression of the inducible nitric oxide synthase (iNOS), impairs beta-cell function, and induces apoptosis. We performed a mutational scanning of all 27 exons of the human NOS2 gene and linkage transmission disequilibrium testing of identified NOS2 polymorphisms in a Danish nationwide type 1 diabetes mellitus (IDDM) family collection. Mutational screening was performed using PCR-amplified exons, followed by single stranded conformation polymorphism and verification of potential polymorphisms by sequencing. The transmission disequilibrium test was performed in an IDDM family material comprising 257 Danish families; 154 families were affected sibling pair families, and 103 families were simplex families. In total, 10 polymorphisms were identified in 8 exons, of which 4 were tested in the family material. A C/T single nucleotide polymorphism in exon 16 resulting in an amino acid substitution, Ser(608)Leu, showed linkage to IDDM in human leukocyte antigen DR3/4-positive affected offspring (P = 0.008; corrected P = 0.024). No other distorted transmission patterns were found for any other tested single nucleotide polymorphism or constructed haplotypes with the exception of those including data from exon 16. In conclusion, linkage of the human NOS2 gene to IDDM in a subset of patients supports a pathogenic role of nitric oxide in human IDDM.
 ...
PMID:Linkage of the human inducible nitric oxide synthase gene to type 1 diabetes. 1139 89

The human major histocompatibility complex (MHC), or human leukocyte antigen (HLA) region, encompasses over 4 Mb of DNA on the short arm of chromosome 6 and is traditionally divided into the class I, class II and class III regions. The MHC has now been entirely sequenced and ~220 genes have been defined of which ~62 are in the class III region. It is becoming clear that many of the latter encode proteins that are likely to be involved in the immune and inflammatory responses. The MHC is known to contribute to a large number of immune-related disorders including insulin dependent diabetes mellitus, rheumatoid arthritis, common variable immunodeficiency and IgA deficiency and there is growing evidence that genes within the class III region are important in determining susceptibility to many of these complex conditions. Genes in the class III region have also been implicated in a number of non-immune-related diseases such as congenital adrenal hyperplasia and sialidosis. Now that the full gene content of the class III region is known the stage is set for the identification and characterisation of candidate disease genes, which will allow greater understanding of the causes of many MHC-linked diseases and thus aid the development of improved treatments.
 ...
PMID:Genetic organization of the human MHC class III region. 1148 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>