Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007570 (celiac disease)
 13,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Celiac disease (CD) is characterized by a striking expansion of gamma delta T cells in the intestine. These cells interact with MICA, a cell surface protein encoded by a major histocompatibility complex gene. We investigated whether MICA gene polymorphism could contribute to susceptibility to CD. DNA typing for HLA-DR, DQA1, DQB1, TNF-308, TNFa, TNFb and a triplet repeat polymorphism in the transmembrane region of the MICA gene were carried out. We performed case-control stratified association studies and transmission disequilibrium tests. Our results indicate that although there is no primary association between MICA polymorphism and CD, there is, in addition to HLA-DQ, a second susceptibility locus on the 8.1 ancestral haplotype in strong linkage disequilibrium with MICA A5.1 allele.
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PMID:Triplet repeat polymorphism in the transmembrane region of the MICA gene in celiac disease. 1207 13

Assays to measure the binding capacity of peptides for HLA-DQA1*0501/B*0201 (DQ2.3) and DQA1*0301/B*0302 (DQ3.2) were developed using solubilized MHC molecules purified from EBV-transformed cell lines. These quantitative assays, based on the principle of the inhibition of binding of a high-affinity radiolabeled ligand, were validated by examining the binding capacity of known DQ-restricted epitopes or ligands. The availability of these assays allowed an investigation of patterns of cross-reactivity between different DQ molecules and with various common DR molecules. DQ2.3 and DQ3.2 were found to have significantly overlapping peptide binding repertoires. Specifically, of 13 peptides that bound either DQ2.3 or DQ3.2, nine (69.2%) bound both. The molecular basis of this high degree of cross-reactivity was further investigated with panels of single substitution analogs of the thyroid peroxidase 632-645Y epitope. It was found that DQ2.3 and DQ3.2 bind the same ligands by using similar anchor residues but different registers. These data suggest that in analogy to what was previously described for HLA-DR molecules, HLA-DQ supertypes characterized by largely overlapping binding repertoires can be defined. In light of the known linkage of both HLA-DQ2.3 and -DQ3.2 with insulin-dependent diabetes mellitus and celiac disease, these results might have important implications for understanding HLA class II autoimmune disease associations.
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PMID:The HLA molecules DQA1*0501/B1*0201 and DQA1*0301/B1*0302 share an extensive overlap in peptide binding specificity. 1239 Dec 26

In B cells, HLA-DO controls HLA-DM-mediated peptide loading on MHC class II molecules. We analyzed whether HLA-DO mutations are associated with autoimmune diseases characterized by an autoantibody component and with a linkage to HLA-DR or HLA-DQ. These diseases include systemic lupus erythematosus, rheumatoid arthritis, celiac disease, and Graves' disease. In addition, several B-cell leukemias were screened for mutations in HLA-DO. A limited number of polymorphisms in DOA and DOB were found, most of which are non-coding changes or result in a conserved amino acid change. A novel non-conserved Arg to Cys mutation in DOA was found in a patient suffering from chronic lymphocytic leukemia. Further analysis did not reveal any effect on the function of HLA-DO. We conclude that HLA-DO variants are not critically involved in the autoimmune diseases and B-cell leukemias studied here.
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PMID:Novel polymorphisms in HLA-DOA and HLA-DOB in B-cell malignancies. 1243 22

Genetic susceptibility to celiac disease is strongly associated with HLA-DQA1*05-DQB1*02 (DQ2) and HLA-DQA1*03-DQB1*0302 (DQ8). Study of the HLA associations in patients not carrying these heterodimers has been limited by the rarity of such patients. This European collaboration has provided a unique opportunity to study a large series of such patients. From 1008 European coeliacs, 61 were identified who neither carry the DQ2 nor DQ8 heterodimers. Fifty seven of these encoded half of the DQ2 heterodimer. The remaining 4 patients had a variety of clinical presentations. Three of them carried the DQA1*01-DQB*05 haplotype as did 20/61 of those carrying neither DQ2 nor DQ8. This may implicate a role of the DQA1*01-DQB*05 haplotype. None of these four patients carried the DQB1*06 allele that has previously been reported in this sub-group of patients. Of the 16 DQ2 heterodimer negative patients without DRB1*04 or DRB1*07 haplotypes, it was inferred that none encoded the previously implicated DRB4 gene as none had a DRB1*09 haplotype. These results underline the primary importance of HLA-DQ alleles in susceptibility to celiac disease, and the extreme rarity of celiac patients carrying neither the DQ2 or DQ8 heterodimers nor one half of the DQ2 heterodimer alone.
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PMID:HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. 1265 Oct 74

Although HLA-DQ genes are the major celiac disease (CD) susceptibility genes, results from Finnish families suggest that not all DQ2-encoding haplotypes confer equal susceptibility to CD, implying the effect of other gene(s) in the HLA region. The aim of the present work was to extend and confirm the aforementioned results in a southern European population ( Italian) and to better localize the additional risk factor/s. The association of nine loci spanning the HLA region from DR to HFE, 4.5-Mb telomeric of HLA-A, was tested. The analysis was performed by comparing marker frequencies in DR3-DQ2 haplotypes transmitted and non-transmitted to the affected offspring in 156 Italian CD families selected for having at least one DR3-positive parent. The same analysis was performed independently in 101 Finnish CD families selected with the same criteria. Three alleles, MICA-A5.1, MICB-CA24 and MIB-350, all characteristic of the B8-DR3 extended haplotype, showed a significantly increased frequency in DR3 transmitted haplotypes in the Italian families. DR3 haplotypes carrying the combination of these alleles conferred an approximate fourfold increased CD risk. B8-DR3 transmitted haplotypes were significantly more conserved telomerically down to the MIC-Class I region. Similar results were seen in the Finnish families. The major conclusion that holds true in both populations is that, while DQ2 is an absolute requirement for the development of CD, the presence of an additional genetic factor within the MIC-Class I region confers an approximate 4-fold increased risk of the disease.
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PMID:Additional factor in some HLA DR3/DQ2 haplotypes confers a fourfold increased genetic risk of celiac disease. 1275 69

Celiac disease (CD) or gluten-sensitive enteropathy is strongly associated with HLA-DQ alleles; more than 95% of patients are DQB1*02. However, the uniform association with HLA-DQ alleles does not explain the clinical heterogeneity, especially the wide range in the age of onset of CD. We asked whether the age of onset of CD is also influenced by class I genes of the human MHC. We performed HLA typing in three groups of patients suffering from CD. The age of onset in the first group (N = 200) was before 15 years of age, in the second group (N = 62) between 15 and 40 years, in the third group (N = 59) after 40 years. We observed a statistically significant increase in the frequencies of HLA-B8 and Cw7 with increasing age of onset. In conclusion, we conclude that distinct alleles from the class I region of the human MHC might lead to late onset of CD. In particular, relatives of CD patients with the disease-prone HLA class I alleles HLA-B8 and Cw7 should be followed up carefully for late onset of CD.
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PMID:Distribution of HLA class I alleles differs in celiac disease patients according to age of onset. 1275 79

Certain HLA-DQ alleles are known to contribute to predisposition to coeliac disease (CD). The existence of additional independent risk-modifying loci in the HLA complex is still being debated. The DR3-DQ2 haplotype has been studied most, but the evidence is conflicting. The discrepancies may stem from the absence of such an effect, insufficient statistical power to detect an effect (i.e. small studies) and/or incomplete control of linkage disequilibrium (LD) to the neighbouring DQ-loci, known to elicit a strong effect. In the present study, we aimed to undertake a statistically high-powered family-based analysis, fully controlling effects of LD between the major DQ-risk haplotypes and neighbouring candidate loci. We investigated five markers on DR3-DQ2, DR5-DQ7 and DR7-DQ2 haplotypes in 327 Norwegian and Swedish families. Our primary finding was that TNF-308A ( TNF2) was significantly associated on the DR3-DQ2 haplotype [stratum specific odds ratio (OR) = 2.40 (1.25-4.48), Pc = 0.009, where P(c) = Pn and n = number of tests performed]. Furthermore, we confirmed earlier indications that LD between TNF2 and DQA1*05-DQB1*02 on the DR3 haplotype is more strongly maintained in family-based cases than family-based controls. In conclusion, we confirmed in this study, the largest of its kind, that additional CD risk factors independent of DQ2 alleles do exist on the DR3 haplotype.
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PMID:Coeliac disease patients carry conserved HLA-DR3-DQ2 haplotypes revealed by association of TNF alleles. 1284 2

Several studies have shown the existence of an association between celiac disease (CD) and non-Hodgkin's lymphoma (NHL). Our aim was to evaluate the usefulness of the serum anti-tissue transglutaminase (anti-tTG) antibody assay in screening for CD in consecutive NHL patients. In all, 80 consecutive patients (median age 61 years) with a new diagnosis of NHL were included. To compare the frequency of CD and of positive results for the anti-tTG assay, we enrolled 500 blood donors. In all patients serum anti-tTG was determined with two different ELISA: one based on tTG from guinea pig (gp-tTG) and the other based on human recombinant t-TG (h-tTG) as the antigens. Serum anti-endomysial antibodies (EmA) were also assayed. Subjects with positive serum EmA and/or anti-tTG underwent intestinal biopsy for histology study, HLA-DQ phenotype determination, and serum anti-gliadin (AGA) assay. Eight of 80 (10%) NHL patients were positive for anti-tTG ELISA--two of these exclusively for anti-gp-tTG and six for anti-h-tTG (7.5%). None of the 80 NHL patients were positive for serum EmA. The frequency of anti-tTG positivity in the blood donor controls was 2/500 (0.4%), significantly lower than that observed in the NHL patients (P < 0.0001). Both these blood donors were found to have CD. Only in one anti-h-tTG-positive NHL patient was there intestinal mucosa atrophy, and follow-up confirmed a CD diagnosis (CD frequency in NHL patients is 1.2%; versus blood donors: P = 0.4). In all the other seven anti-tTG-positive NHL patients a normal intestinal architecture was found, although, inflammatory infiltration of the lamina propria was observed in four patients. No anti-tTG-positive NHL patients, including the subject diagnosed as having CD, had a family history of CD, and all had normal weight and no signs of malabsorption. Anti-tTG false positive results were associated with a higher frequency of serum autoantibody positivity and T-cell type NHL. In conclusion, NHL patients the anti-tTG assay often gives discordant data with the EmA assay, with a high frequency of anti-tTG false positive results for CD diagnosis.
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PMID:Screening for celiac disease in non-Hodgkin's lymphoma patients: a serum anti-transglutaminase-based approach. 1292 48

The description of a range of antibodies associated with coeliac disease has been an important development in the ability to test for this common and treatable condition non-invasively. However, the detection of these antibodies remains unstandardised and the appreciation of the clinical utility of each is evolving. In view of the advances in the diagnosis and understanding of coeliac disease, we discuss: (1) the relative advantages, disadvantages and comparative diagnostic utility of the different antibody tests including the confounding effect of selective IgA deficiency; (2) various technical aspects of these tests; (3) HLA-DQ typing as a supplementary tool to antibody testing; (4) areas of controversy resulting from insufficient or conflicting published data; and (5) potential testing strategies.
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PMID:Antibody and genetic testing in coeliac disease. 1520 42

In patients with celiac disease, inflammatory T cell responses to HLA-DQ2-bound gluten peptides are thought to cause disease. Two types of HLA-DQ2 molecules exist, termed HLA-DQ2.5 and HLA-DQ2.2. Whereas HLA-DQ2.5 predisposes to celiac disease, HLA-DQ2.2 does not. We now provide evidence that the disease-associated HLA-DQ2.5 molecule presents a large repertoire of gluten peptides, whereas the non-disease-associated HLA-DQ2.2 molecule can present only a subset of these. Moreover, gluten presentation by HLA-DQ2 homozygous antigen-presenting cells was superior to presentation by HLA-DQ2/non-DQ2 heterozygous antigen-presenting cells in terms of T cell proliferation and cytokine secretion. Gluten presentation by HLA-DQ2.5/2.2 heterozygous antigen-presenting cells induced intermediate T cell stimulation. These results correlated with peptide binding to the antigen-presenting cells. Finally, we demonstrate that HLA-DQ trans dimers formed in HLA-DQ2.5/2.2 heterozygous individuals have properties identical with HLA-DQ2.5 dimers. Our findings explain the strongly increased risk of disease development for HLA-DQ2.5 homozygous and HLA-DQ2.2/2.5 heterozygous individuals, and they are indicative of a quantitative model for disease development, where HLA-DQ expression and the available number of T cell-stimulatory gluten peptides are critical limiting factors. This model may have important implications for disease prevention.
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PMID:The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. 1453 Mar 92


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