Risk Factors For Celiac Disease Research Articles

Autoimmune diseases: insights from genome-wide association studies

Autoimmune diseases occur when an individual's own immune system attacks and destroys his or her healthy cells and tissues. Although it is clear that environmental stimuli can predispose someone to develop autoimmune diseases, twin- and family-based studies have shown that genetic factors also play an important role in modifying disease risk. Because many of these diseases are relatively common (prevalence in European-derived populations: 0.01-1%) and exhibit a complex mode of inheritance, many DNA sequence variants with modest effect on disease risk contribute to the genetic burden. Recently, the completion of the HapMap project, together with the development of new genotyping technologies, has given human geneticists the tools necessary to comprehensively, and in an unbiased manner, search our genome for DNA polymorphisms associated with many autoimmune diseases. Here we review recent progress made in the identification of genetic risk factors for celiac disease, Crohn's disease, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and type-1 diabetes using genome-wide association studies (GWAS). Strikingly, GWAS have increased the number of genetic risk variants associated with these autoimmune diseases from 15 before 2006 to 68 now. We summarize what this new genetic landscape teaches us in terms of the pathogenesis of these diseases, and highlight some of the outstanding challenges ahead. Finally, we open a discussion on ways to best maximize the impact of these genetic discoveries where it matters the most, that is for autoimmune disease patients.

Aberrant extrathymic T cell receptor gene rearrangement in the small intestinal mucosa: a risk factor for coeliac disease?

Background:Coeliac disease is a small intestine enteropathy caused by permanent intolerance to wheat gluten. Gluten intake by patients with coeliac disease provokes a strong reaction by intestinal intraepithelial lymphocytes (IELs),...

Myosin IXB gene region and gluten intolerance: linkage to coeliac disease and a putative dermatitis herpetiformis association

Background:Coeliac disease is caused by dietary gluten, which triggers chronic inflammation of the small intestine in genetically predisposed individuals. In one quarter of the patients the disease manifests in the...

Identification of a non-HLA genetic risk factor for celiac disease

Identification of a non-HLA genetic risk factor for celiac disease

Update on the evaluation and diagnosis of celiac disease

Our understanding of the pathophysiology of celiac disease has advanced with associated improvement in diagnostic modalities. Recent studies have placed the prevalence of celiac disease in Western populations at between 1:250 and 1:67. Celiac disease is common throughout the world and most cases go undiagnosed. Understanding the risk factors, clinical presentations and diagnostic modalities is necessary to identify and treat patients with this commonly misdiagnosed disorder. Increased prevalence of celiac disease in individuals with autoimmune diseases, reduced bone mineral density and undiagnosed liver disease have been confirmed. However, celiac disease may not be associated with Down's syndrome or epilepsy. Evidence supports high sensitivity and specificity of endomysial- and tissue transglutaminase-based tests in most settings. In children, high or low tissue transglutaminase levels may preclude the need for duodenal biopsy. Cost-effectiveness studies suggest using tissue transglutaminase or endomysial initially, while distal duodenal or jejunal biopsy may confirm celiac disease in the absence of proximal changes. There is insufficient evidence to support mass screening for celiac disease. However, case finding in individuals with risk factors for celiac disease is recommended. Further study is necessary to define diagnostic algorithms and target populations likely to benefit from testing.

When and how should gluten be introduced into the infant's diet

Coeliac disease (CD), or permanent gluten-sensitiveenteropathy, develops because tolerance to ingestedwheat gluten (gliadins and glutenins) and relatedproteins from wheat rye and barley never develops,or is broken after it has developed. CD is char-acterized by inflammation of the small intestine,resulting in crypt hyperplasia, villous atrophy andflattening of the mucosa. Other characteristics arean increased number of intraepithelial lymphocytes(IELs) and lamina propria lymphocytes, increasedserum concentrations of immunoglobulin A (IgA)antibodies towards gliadin and the autoantigentissue transglutaminase. When gluten is withdrawnfrom the diet the mucosal morphology is restored,the specific antibody levels become normal andsymptoms of the disease disappear (1). CD is anacquired disorder, which can be diagnosed fromearly infancy with classical symptoms such asdiarrhoea, malabsorption and failure to thrive, toadulthood with a wider and more diffuse spectrumof symptoms (2). Poor dietary compliance andundiagnosed disease, which is frequent in adultpopulations, are associated with increased morbid-ity and mortality (3).CD is a chronic inflammatory disease with astrong polygenic component, although most of thegenes involved are still unknown (4). Over 90% ofpatients express the major histocompatibility com-plex (MHC) class II molecule HLA-DQ2 and theremainder usually HLA-DQ8, both of which pre-dispose for the disease (5). Exposure to gluten orcertain peptides thereof, in genetically predisposedindividuals, is a prerequisite for CD development,and once established the disease can be turned onand shut off by introducing gluten into or with-drawing gluten from the diet. CD is associated withan abnormal T-cell-initiated immune response togluten, but the detailed pathogenesis still remains tobe elucidated. The Swedish epidemic of CD withclassical symptoms in children below 2 years of age,which surfaced for a little longer than a decade fromthe mid-1980s, strongly supports an aetiological roleof environmental factors, such as early infantfeeding practices (6, 7), and thus a multifactorialaetiology.Large amounts of gluten: independent riskfactorThe recent Swedish incident case-referent studycontributed to the identification of some of thesecausal environmental risk factors. For the first timethe design of the study allowed assessment of theconsumption of gluten-containing cereals on anindividual level (8). Introduction of gluten-contain-ing foods in large amounts, compared with small ormedium amounts, was an independent risk factorfor CD development [adjusted odds ratio (OR) 1.5,95% confidence interval (CI) 1.1

Evaluation of cytokine polymorphisms (TNFα, IFNγ and IL-10) in Down patients with coeliac disease

Background In Down syndrome there is an increased prevalence of coeliac disease, but the reasons for this association are yet unknown. Aims To evaluate a possible correlation between TNFα, IFNγ and IL-10 genotype polymorphisms with the susceptibility to coeliac disease in Down syndrome patients. Methods Single nucleotide polymorphisms of TNFα (−308G → A promoter region), IFNγ (+874T → A promoter region) and IL-10 (−1082G → A promoter region) have been studied in 10 Down patients with coeliac disease, in 40 Down patients without coeliac disease and in 220 healthy controls. Clinical features were also studied in coeliac disease–Down syndrome patients. Results The 10 coeliac disease–Down syndrome patients had a biopsy proven coeliac disease afterward a serological testing positive to antigliadin, antiendomysium and antitransglutaminase antibodies. Intestinal biopsy showed total atrophy in 6/10 and partial villous atrophy in 4/10 of them. All coeliac disease–Down syndrome patients had silent forms of coeliac disease and classical trisomy 21. No significant differences were observed for the IFNγ and IL-10 polymorphisms in the studied groups. A significant trend for increase of TNFα −308A positive frequency was observed in coeliac disease–Down syndrome patients compared to healthy controls ( p = 0.043). Conclusions Single nucleotide polymorphisms of IFNγ and IL-10 do not play a role in predisposing Down syndrome patients to coeliac disease, while the TNFα −308 allele could be an additional genetic risk factor for coeliac disease in trisomy 21.

Epidemiological and clinical features in immigrant children with coeliac disease: an Italian multicentre study

Background. There are no available data concerning the incidence and the clinical pattern of coeliac disease in immigrant children coming to Italy from developing countries. Aims. To evaluate the epidemiological and clinical features of coeliac immigrant children coming to Italy. Patients and methods. Hospital records of 1917 children diagnosed in 22 Italian Centres from 1999 to 2001 as having coeliac disease were retrospectively reviewed, comparing immigrant patients versus Italian ones. Results. 36/1917 (1.9%) coeliac children were immigrant. This prevalence was similar to that of the immigrant children among the whole paediatric population living in Italy. Prevalence was influenced by geographical factors, being higher in Northern Italy (1.7%) and in Central Italy (2.5%) than in Southern–Insular Italy (1.5%), as consequence of a higher proportion of immigrants in these regions. The native areas of the immigrant children were East Europe (15/36), Northern Africa (14/36), Southern Asia (4/36), West Africa (1/36), East Africa (1/36) and the Middle East (1/36). The clinical spectrum and dietary habits in immigrant patients were similar to those of the Italian children. Conclusions. Coeliac disease among the immigrant children coming from developing countries is an emerging problem, and physicians need to be fully aware of it. An important risk factor for coeliac disease in immigrant children appears to be sharing of the same dietary habits with the Italian population. The finding of coeliac disease in children coming from many countries worldwide suggests that coeliac disease is a global public health problem.

Meta and pooled analysis of European coeliac disease data.

Four full genome scans have been carried out by the partners of the European cluster on coeliac disease as well as follow-up studies of candidate regions. No region outside HLA showed significant linkage to the disease in any single study. We first applied a meta-analysis based on a modification of Genome Screen Meta-Analysis to take into account the different linkage statistics, the arbitrariness of bin cutoff points, as well as the sample size of each study. We then performed a pooled linkage analysis of all families and raw genotypes. Besides the HLA region, already known to harbour a risk factor for coeliac disease, both approaches leave very little doubt on the presence of a genetic risk factor in the 5q31-33 region. This region was suggested by several individual studies, but did not reach statistical values high enough to be conclusive when data sets were analysed separately.

A collaborative European search for non- DQA1*05-DQB1*02 celiac disease loci on HLA-DR3 haplotypes: analysis of transmission from homozygous parents

The HLA-DQA1*05 with DQB1*02 alleles are a major risk factor for celiac disease (CD). To search for additional human leukocyte antigen (HLA) risk factors, we looked on the DR3-DQ2 risk haplotype, selected because it carries both DQ risk alleles in cis and is the more represented among CD patients. In a European consortium, we identified 109 families with a parent homozygous for DQA1*05-DQB1*02. We typed ten microsatellites in the extended HLA complex, and applied the homozygous-parent transmission disequilibrium test (HPTDT) and extended-TDT to transmissions from homozygous parents. These methods eliminate confounding due to linkage disequilibrium between candidate disease loci and the known risk factor DQA1*05-DQB1*02, and are favorable when sufficient families are available. We did not find evidence of association with any single marker or allele, although weak evidence for additional risk was observed, represented by preferential transmission of six adjacent markers. We tested the largest ever reported HPTDT population in CD, providing unprecedented power. We did not find significant evidence of additional risk-modifying factors on the DR3 haplotype, independent of DQA1*05-DQB1*02, although a weak tendency was observed for the B8-DR3 haplotype. This effect should be tested in large populations with significant representations of both B8-DR3 and non-B8 DR3 haplotypes.

Enterovirus Infection During Pregnancy is Not a Risk Factor for Celiac Disease in the Offspring

ABSTRACTBackgroundThere is a strong genetic influence on the susceptibility to celiac disease but it is also evident that environmental factors play a role in the development of the disease. Diverging studies about adenovirus infection as a possible triggering factor in the pathogenesis have been reported. Our study was undertaken to determine whether enterovirus infection during pregnancy is a risk factor for the development of celiac disease later in childhood.MethodsCord blood from 76 mothers whose children developed celiac disease before 15 years of age were analyzed for IgA, IgG, and IgM antibodies for enteroviruses and Ig‐A endomysium antibodies. The control group comprised cord blood from 327 mothers with children without known celiac disease.ResultsThere were no significant differences in antibody titers for enterovirus between the two groups. IgA‐endomysium antibodies were elevated in 3 of the 76 mothers, whereas none had known celiac disease.ConclusionThis study does not show that enterovirus infection during pregnancy is associated with the development of celiac disease in childhood. Of the mothers whose children developed celiac disease, 4% had Ig‐A endomysium antibodies, which may reflect a silent celiac disease.

Not all HLA DR3 DQ2 Haplotypes Confer Equal Susceptibility to Coeliac Disease: Transmission Analysis in Families

Background: HLA-DQ is the only established susceptibility factor for coeliac disease. We tested whether all HLA haplotypes with the known risk marker, HLA-DQ2, confer equal susceptibility to coeliac disease, i.e. whether haplotype transmission from DQ2 homozygous parents to patients is random. The random transmission would strengthen the importance of DQ2 as the only risk factor within the HLA region. Methods: Inheritance of DQ2-positive haplotypes from parent to patients was investigated in 14 of 127 Finnish coeliac families who had an HLA-DQ2 homozygous parent. HLA alleles and 18 HLA-linked microsatellite markers were used to determine the haplotypes, which were divided into those transmitted and those non-transmitted from DQ2-homozygous parents to patients. Results: Transmitted haplotypes differed clearly from those not transmitted. The alleles in the transmitted haplotypes were strongly conserved and predominantly consisted of the well-known HLA-A*01, B*08, DRB1*03, DQ2, DPB1*0101 haplotype. The non-transmitted haplotypes, on the other hand, were significantly more heterogeneous; in particular, markers near HLA-A and-B genes differed from the transmitted haplotypes. Conclusions: The results suggest that DQ2 is not the only HLA-linked genetic risk factor for coeliac disease but the conserved haplotype harbours at least one other risk gene.

Study of HLA-DQB1 alleles in Spanish celiac patients and their first-degree relatives

Celiac disease (CD) susceptibility is strongly associated with the HLA alleles DQA1 0501 and DQB1 02*. To investigate this, we performed a study which included thirty celiac children and sixty-five first-degree relatives of them. DQB1 genotyping was performed by PCR (polymerase chain reaction) amplification. The allele frequencies in each group were compared by Chi-square test (χ2) using Yates correction and Fisher test. Most patients (70%) were positive for DQB1 0201. HLA-DQB1 0201 was found in 61% of the first-degree relatives. 58% of the patients showed heterozygosity for DQB1 0201, whereas 12% of the celiac patients were homozygous for DQB1 0201. These findings support the role of DQB1 0201 alleles as a risk factor for celiac disease. No significant differences could be detected in the HLA-DQB1 allele distribution between celiac patients and their first-degree relatives.