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Short arm of chromosome 6 Map of the MHC.
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Recent studies using the technique of the human genome screening in families with multiple siblings suffering from coeliac disease have suggested the presence of at least four different chromosomes in the predisposition to suffer from coeliac disease. Two loci in chromosome 6 appear to be important in disease susceptibility. Other studies based on...
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... the first-established association was made with class I molecules of the HLA system (HLA-B8) and with class II molecules (HLA-DR3 in northern Europe HLA- DR5/-DR7 in the south), the common base is the association with the HLA-DQ2 (11). HLA-DQ2 is present in 90 to 95% of the patients with coeliac disease and in 20 to 30% of the healthy European control group. Coeliac disease is primarily associated with the combination of two HLA-DQ alleles, the HLA-DQA1*0501 and the HLA-DQB1*02, arranged either in a cis or trans configura- tion in the majority of patients, whereas a minority carry the HLA-DR4 associated DQB1*0302, serologically known as HLA-DQ8 antigen. In spite of the very close association between the HLA system and coeliac disease, other genes within chromosome 6, such as the TNF genes (12), may influence the severity of the disease ( Fig. 1). Tumour necrosis factor alpha (TNF alpha), lymphotoxin alpha (TNF beta), and interleukin-1 receptor antagonist (IL- 1ra) have been investigated. These cytokines are small polypeptides important in regulating proliferation, differen- tiation, and function of cells. They function as chemical messengers between cells of the immune, inflammatory and other systems and are therefore important in immune response, inflammation, and fibrosis. A balance between levels of cytokines, their receptors, and inhibitors controls inflammatory reactions. Using molecular typing techniques we have recently studied 4 polymorphisms at the TNF a /LT a locus. Bi-allelic polymorphisms in these loci are arranged in haplotypes and we established that 5 TNF haplotypes are present in the Dutch population (Fig. 2). We have found that in patients with coeliac disease, haplotype TNF-E is increased ( P = 0.0001) (Fig. 3). Although large inter-individual differences in intrinsic capacity to produce TNF a and LT a exist, it seems that differences in secretion are related to polymorphisms in the TNF region. Position-308 (TNF-E) plays an important role in the regulation of TNF a secretion. Since the ‘high secretor’ haplotype TNF-E is significantly associated with coeliac disease we have postulated that this may represent the genetic basis for the chronic inflammatory response in the small-bowel tissue of CD patients. Studies to verify this hypothesis are under way. Haplotype TNF-E may be related to severity or other clinical characteristics of CD. Recent studies using the molecular biology technology of chromosome-wide screening the genes of the entire genome in coeliac concordant families have confirmed the involve- ment of various chromosomes in the predisposition to the disease (13). In this study, performed in families in the western counties of Ireland, it was found that in chromosome 6 there was another locus outside the HLA region that was important in defining the susceptibility. There were other regions of possible influence in chromosome 11p, 7q, and chromosome 22 near the ...
Citations
... In contrast to gluten sensitivity celiac disease development has a strong genetic component with a sibling relative risk (lambda (s)) of 30. Recent studies using the human genome screening technique in families with multiple siblings suffering from CD have suggested the presence of at least 4 different chromosomes in the predisposition to suffer from CD (17). One susceptibility locus is the MHC (major histocompatibility complex) region, with a particular association with the HLA-DQ alleles DQA1*0501 and DQB1*0201. ...
Atypical presentation is the most common form of celiac disease (CD). Although the terminologies like latent, silent and potential have expressed different aspects of clinical and pathological behaviour of CD, they also have contributed in some extent to confusion between clinicians and patients due to the multiple definitions and uncertainty around them. In the light of new advances and the discovery of entities such as non-celiac gluten sensitivity, using subclinical instead of silent and atypical instead of potential/latent may simplify the understanding behind the clinical behaviour of atypical CD. The evidence behind a lower threshold for starting a gluten free diet (GFD) in non-celiac gluten sensitive patients would strongly support applying a GFD treatment strategy in any forms of CD.
... Celiac disease (CD) is a common autoimmune disorder with a prevalence of 1 in 200-300 in Europe and North America, with the highest incidence in western European countries [10,11]. The female to male ratio is 2/1. ...
Human leukocyte antigen (HLA) phenotype DQ2 is considered the most important genetic marker for un-responsiveness to hepatitis B vaccine. Since celiac disease (CD) is also strongly associated with the same haplo-type it may be hypothesized that celiac patients are less able to respond to the vaccine. We report a retrospective study on celiac patients vaccinated with three doses of 10 microg at 3, 5 and 11 months of age by an intramuscular injection of a recombinant hepatitis B vaccine (Engerix B). We found 30 of 60 celiac patients (50%) unresponsive to vaccination and a significant higher number of responders among patients younger than 18 months at the time of celiac disease diagnosis. Our study confirms that celiac patients have a lower percentage of response to hepatitis B vaccination than healthy subjects. These findings provide useful information to evaluate if current vaccine strategies should be reassessed and if revaccination should be recommended.
... Polymorphisms in TNF genes have been associated with susceptibility to several autoimmune diseases, such as juvenile idiopathic arthritis, systemic lupus erythematosus, dermatitis herpetiformis and CD. Most studies have concluded that the association between TNF2 and autoimmune disease may be explained through linkage disequilibrium [21][22][23][24][25]. In contrast, some reports suggest that TNF2 gene is independently associated with an increased risk for CD in HLA-DR3-DQ2 positive patients [26,27]. ...
Coeliac disease (CD) is common in patients with microscopic colitis (MC). The human leucocyte antigen (HLA)-DR3-DQ2 haplotype is strongly associated with CD, and there is evidence for an association with MC. We analysed the genetic background of MC by assessing the haplotypes of HLA-DR3-DQ2 and HLA-DR4-DQ8. In addition, TNFalpha gene polymorphism (-308) associated with susceptibility to several autoimmune diseases was studied.
Eighty patients with MC including 29 with collagenous colitis (CC) and 51 with lymphocytic colitis (LC) were typed for HLA-DR3-DQ2, and HLA-DR4-DQ8 molecule encoding genes using either an allele-specific PCR, or hybridization with sequence-specific oligonucleotides. Duodenal biopsies (N=78) confirmed the diagnosis of CD in 15 (18.8%) patients. TNFalpha(308) alleles were analyzed in 78 patients with MC (27 with CC and 51 with LC). A control group of 3627 patients was used in the HLA study and 178 patients in the TNFalpha study.
HLA-DR3-DQ2 haplotype was more frequent in patients with MC (43.8%) including both subgroups (LC, 44.8%; CC, 43.1%; P<0.001), and MC with CD (86.7%; P<0.001) and without CD (33.3%; P=0.003), compared with the controls (18.1%). Similarly, the TNF2 carrier rate was higher in MC (46.2%; P<0.001) including both CC (44.4%; P=0.031) and LC (47.1%; P=0.001), and both MC patients with CD (66.7%; P=0.001) and without CD (39.3%; P=0.019), compared with the controls (23%).
Both CC and LC are associated with the HLA-DR3-DQ2 haplotype and with TNF2 allele carriage. These associations are present also in MC patients without CD. The shared predisposing HLA-DR3-DQ2 haplotype and the high prevalence of CD in patients with MC suggest an epidemiological overlap, and probably some similarities in the pathogenesis of CD and MC.
... Our data confirm that all diabetic children should be screened for CD, particularly if they have stunted growth. Growth impairment may be the result of nutritional deficiencies, mediators of chronic inflammation such as y interferon and tumor necrosis factor-α (1,41) , or other factors. ...
... The correlation between either tTG and EmA antibody titers and severity of intestinal injury, demonstrated in this study, suggests that antibodies may have a role in immunologic injury, even though such injury is cellmediated (41) . ...
Background /Aim: Diagnosis of atypical and silent celiac disease (CD) is important because of its serious complications. The association of type 1 diabetes and CD has been reported worldwide. The aim of this study was to determine the prevalence and clinical, biochemical and histopathologic characteristics of CD among Egyptian children and adolescents with type 1diabetes. Subjects and methods: A total of 116 children and adolescents with type 1 diabetes (62 males and 54 females, age rage 2-21 yrs) and 25 age and sex matched healthy children were screened for CD using anti-gliadin (AGA), anti-tissue transglutaminase (t-TG), anti-reticulin (AGA) and anti-endomysial (EmA) antibodies. Clinical data, hemoglobin Alc, insulin requirements, hemoglobin concentration, mean red cell volume and serum ferritin levels were evaluated. Results: Twenty-six (22.4%) patients were positive for AGA and t-TG antibodies, 14 of them were ARA positive. Ten of these patients were EmA positive and four were EmA negative. From the EmA negative patients three sera with IgA deficiency had high IgG class in AGA, anti-t-TG and ARA antibodies. All these 14 patients (EmA positive and negative) underwent intestinal biopsy. Thirteen had histological evidence of CD including the EmA negative patients with IgA deficiency, giving a prevalence of CD in diabetic children of 11.2% (13/116). Compared with the other diabetic patients, those with CD had a significantly higher height SD scores with no statistical significant changes in any other parameters Conclusion: the prevalence of CD in Egyptian type 1 diabetes children and adolescents was found to the high. Serologic markers for CD are useful for identifying asymptomatic type 1 diabetes children who should undergo a small intestinal biopsy.
... Celiac disease (CD) is characterized by an evident involvement of the immune response similar to the one observed in autoimmune diseases (1). Although CD is almost exclusively associated with the HLA-DQ heterodimer encoded by DQA1*0501 and DQB1*0201 alleles (2), several studies have investigated whether other genes could predispose to CD (3), as human lymphocyte antigen (HLA) risk factors do not explain the entire genetic susceptibility to gluten intolerance (4,5). ...
Selective IgA deficiency (IgAD) and celiac disease (CD) are frequently associated and share the ancestral haplotype human leukocyte antigen (HLA)-8.1, which is characterized by a peculiar cytokine profile. The aim of this study was to evaluate the role of tumor necrosis factor (TNF) and interleukin (IL)-10 alleles in CD and CD-IgAD.
The distribution of some biallelic polymorphisms of both cytokine promoters (-308G-->A and -863C-->A at TNF promoter sequence and -1082G-->A, -819C-->A, and -592C-->T at IL-10 promoter) were typed using biotilinated specific probes in 32 celiac patients, in 34 CD-IgAD patients, and in 96 healthy controls.
In CD and CD-IgAD, the -308A allele was significantly more frequent than in controls, whereas no significant differences were observed for the biallelic polymorphisms at the -863 and for the three IL-10 promoter polymorphisms. The evaluation of combined TNF and IL-10 genotypes showed in CD-IgAD a significant reduction of -308G/-1082G homozygous subjects and both in CD and CD-IgAD groups an increase of 308AA/1082GG. Accordingly, CD-IgAD patients positive both for -308A TNF and -1082A IL-10 showed an increase of TNF-alpha and a reduction of IL-10 serum levels.
Genetically determined increased production of TNF-alpha and reduction of IL-10 may be relevant for susceptibility to CD, mainly in IgAD, as the different allele expression at TNF and IL-10 loci seems to influence cytokine production profile.
... Polymorphisms in, or near, TNF genes have been associated with susceptibility to several autoimmune diseases. These polymorphisms are linked to high TNF secretion by blood mononuclear cells (Peña et al. 1998). ...
TNFalpha and TNFbeta, or linfotoxin (LTalpha), are two molecules playing an important role in inflammation. Their genes map on Chromosome 6, between the HLA class II and class I loci. Polymorphisms in, or near, TNF genes have been associated with susceptibility to several autoimmune diseases. Studies of TNF genes in celiac disease (CD) have presented contradictory results. We have assessed the role of TNFalpha and linfotoxin alpha (TNFbeta) in CD and their relative value as CD markers in addition to the presence of DQ2. The TNFA -308 polymorphism and the polymorphism at the first intron of the LTA gene were typed in CD patients and healthy controls and the results were correlated with the presence of DQ2. Significant differences were found in genotype and allele frequencies for the TNFA and LTA genes between CD patients and controls, with an increase in the presence of the TNFA*2 and LTA*1 alleles in CD patients. These differences increase when DQ2-positive CD patients and DQ2-positive controls are compared. In DQ2-positive individuals, allele 2 (A) in position -308 of the promoter of TNFA and allele 1 (G) of the NcoI RFLP in the first intron of LTA are additional risk markers for CD.
... A single nucleotide polymorphism (G to A transition) at position -308 in the promoter region of TNFA has been found to increase TNF-a transcription 6-8-fold [10]. The TNFA-308*2 allele appears to be a risk factor for diseases such as asthma, severe malaria, diabetes, or coeliac disease [11][12][13]. Polymorphic microsatellites that flank the TNF genes have also proved to be informative markers of TNF-a production [14,15]. One of these, TNFa, located upstream of TNFB, has been reported to be associated with high (TNFa2) or low (TNFa6, a4) TNF-a production by blood monocytes [14]. ...
In some patients, chemotherapy (CHT) of cancer can result in pulmonary inflammation and fibrosis, eventually leading to respiratory insufficiency. As animal studies have underlined the importance of major histocompatibility complex (MHC) genes in the susceptibility to bleomycin (BLM)-induced pulmonary fibrosis, the authors typed human leukocyte antigen-DR (HLA-DR) and tumor necrosis factor (TNF) genes in patients treated for Hodgkin's disease by a therapy including bleomycin. Patients were divided into pulmonary responders (PR) (n=21) or nonresponders (PNR) (n=20) on the basis of pulmonary alterations detected on chest radiography and the cumulated amount of BLM injected. The incidence of TNFa2, a microsatellite allele in the promoter region of the TNFB gene reported to be associated with increased TNF-a production, was significantly higher in PR than PNR (65% versus 19%). HLA-DRB1*15 showed a weak but nonsignificant association with the PR phenotype (50% versus 14%), as well as HLA-DRB1*03 (30% versus 19%) and TNFA-308*2 (30% versus 14%). TNFa2 and DR15 were independent risk factors and the occurrence of either genetic marker was 85% versus 29% in the PR and PNR groups respectively. Thus, the polymorphic TNFa2 microsatellite is associated with a risk of chemotherapy-induced pulmonary fibrosis.
... Still, no more than 40% of the genetics of GSE can be explained by HLA-DQ, suggesting that a small number of non-HLA-linked genes and/or other genes from the MHC region confer the stronger genetic risk. An investigation using family data proposed that the involvement of two distinct and unlinked genes (an HLAand a non-HLA-linked locus) is necessary for the etiology of GSE [28] . Prerequisites for developing GSE are homozygosity at the non-HLA-linked locus (ie, recessive inheritance) and participation of an independently inherited gene from the MHC system, acting in a dominant fashion. ...
... Prerequisites for developing GSE are homozygosity at the non-HLA-linked locus (ie, recessive inheritance) and participation of an independently inherited gene from the MHC system, acting in a dominant fashion. However, the problem with this original model was that the predicted population prevalence of about 1 in 320 did not agree with the observed frequency (which was much lower at that time) [28]. Although several studies agreed on recessivity at the non-HLA-linked locus, they differed with respect to dominance or recessivity at the HLA-linked locus [29]. ...
Genetic epidemiology clearly has shown that there is a genetic predisposition to gluten-sensitive enteropathy (GSE), or celiac disease. The strong genetic component, as determined by the lambda sib (lambda s), has been calculated to lie in the range of 7.5 to 30, based on a 5% to 10% recurrence risk for siblings. Ninety-five percent of northern European patients with GSE carry a particular HLA-DQ alpha beta heterodimer. Studies support the concept that the HLA-DQ gene acts as a dominant gene, and they also found that, in addition to HLA-DQ, a second locus within the major histocompatibility complex (MHC) is involved in the predisposition to GSE in the Dutch population. Genome scans conducted so far suggest that MHC and non-MHC loci collectively contribute to disease susceptibility. Since one, and probably even two, gene(s) from the MHC region itself determine at least 40% to 50% of the genetic predisposition to GSE, it is expected that the other loci each contribute only a little to the total genetic variation. The exact role of these additional genes (i.e., whether they are involved in the initiation or the progression of the disease) remains to be determined.
... In addition, some of these children with CD developed IDDM during a follow-up of 10 years (2). Furthermore, CD and IDDM are supported by an identical genetic background (class II HLA DR3 and HLA DQ2 genotypes) (1,3,4). Finally, similar mechanisms of 3-cell and enterocyte cell damage medi-ated by tumor necrosis factor and 'y-interferon are observed (4). ...
... Furthermore, CD and IDDM are supported by an identical genetic background (class II HLA DR3 and HLA DQ2 genotypes) (1,3,4). Finally, similar mechanisms of 3-cell and enterocyte cell damage medi-ated by tumor necrosis factor and 'y-interferon are observed (4). ...
... It is widely accepted that immunological mechanisms are involved in the development of the mucosal damage seen in coeliac disease. In untreated patients there are signs of activation of mucosal cellular and humoral immune systems (Sollid 1989, Peña et al. 1998). The principal environmental trigger is ingested gluten, but additional factors may be required. ...
Celiac disease (CD/ Nontropicalsprue, gluten-sensitive enteropathy) is a malabsortive condi- tion in which an allergic reaction to the cereal grain-protein gluten (present in wheat, rye and barley) caus- es small intestine mucosal injury. The onset is in the first four decades of life, with a female to male ratio of 2:1. It may be associated with a wide spectrum of neurological manifestations including cerebellar atax- ia, epileptic seizures, dementia, neuropathy, myopathy and multifocal leucoencephalopathy. We report three patients with neurological manifestations related with CD: one with cerebellar ataxia, one with epilepsy and one with cognitive impairment. The diagnosis of CD was confirmed by serologic tests (antiendomysial and antigliadin antibodies) and biopsy of the small intestine. In two patients the neurological symptoms preceded the gastrointestinal abnormalities and in all of them gluten restriction failed to improve the neu- rological disability. Conclusion: CD should be ruled out in the differential diagnosis of neurological dys- function of unknown cause, including ataxia, epilepsy and dementia. A gluten free diet, the mainstay of treatment, failed to improve the neurological disability.
