Risk Factors For Celiac Disease Research Articles

Celiac Disease: More Common yet “Atypical” than Previously Thought

Celiac disease, an autoimmune enteropathy triggered by the consumption of gluten, can develop in genetically predisposed children (HLA DQ2 and/or DQ8 positive) at any point from 9 months of age through adulthood. Although the incidence of celiac disease in both North America and the bulk of Europe is approximately 1 in 100, patients with a first-degree relative with celiac disease are at a much higher risk of development. For example, up to 25% of children who are homozygous for HLA-DQ2 will develop evidence of celiac autoimmunity by age 6 [1]. Additional risk factors for the development of celiac disease include type 1 diabetes, autoimmune thyroid disease, Trisomy 21, Turner syndrome, William’s syndrome, and selective IgA deficiency [2]. The celiac genes (HLA-DQ2 and DQ8) contribute 40% of the risk of developing celiac. Environmental risk factors for celiac disease include infant feeding patterns, early infections,

Risk factors for celiac disease.

Celiac Disease (CD) is an immune-mediated systemic disorder elicited by gluten and related prolamines in genetically susceptible individuals and it is the result of the interaction between genetic and environmental factors. Among genetic risk factors, the strongest association is with the HLA class II DQ region; nevertheless at least 39 non-HLA loci are associated with CD. Gluten is the main environmental trigger of the disease. In addition, infant feeding and weaning practices as well as timing of gluten introduction in the diet have been suggested to contribute to CD risk. Furthermore a role for infectious agents and microbiota composition in disease development has also been proposed.Aim of this short review is to discuss the current knowledge on both genetic and environmental risk factors for the development of CD; moreover we will provide a brief overview of the possible strategies that could be envisaged to prevent this condition, at least in the population at-risk.

Systematic review and meta-analysis of the association between IL18RAP rs917997 and CCR3 rs6441961 polymorphisms with celiac disease risks

Objectives: We performed a systematic review and meta-analysis to estimate the polymorphism effects of IL18RAP and CCR3 on celiac disease susceptibility. Methods: PubMed and Web of Science databases were searched (to June 2015) on IL18RAP rs917997 and CCR3 rs6441961 polymorphisms. Results: The meta-analysis included 16 and 7 studies for rs917997 and rs6441961, respectively. The minor risk A allele at both rs917997 and rs6441961 carried risks (odds ratios) of 1.24 (95% CI 1.18–1.31) and 1.21 (95% CI 1.12–1.31), respectively. These alleles contributed to increase risks in all celiac disease patients by 5.04 and 6.35%. The estimated lambdas were 0.73 and 0.51, suggesting that an additive model would be the best choice for both gene effects. Conclusions: This meta-analysis provides robust estimates that IL18RAP rs917997 and CCR3 rs6441961 are potential risk factors for celiac disease in European populations. Studies are needed to confirm these findings in different ethnicities.

Age at gluten introduction is not an independent risk factor for coeliac disease

Age at gluten introduction is not an independent risk factor for coeliac disease

Role of Chronic Viral Hepatitis B and C as Risk Factors for Celiac Disease

Aims: Celiac disease (CD) is an autoimmune disease and hepatitis B virus (HBV) is suspected to trigger immunologic gluten intolerance in susceptible individuals. The aim of this study is to assess

Exposure to excessive oral vitamin D in youth: a risk factor for celiac disease in later life?

Celiac disease is an autoimmune disease initiated by an allergic reaction to gliadin a component of the protein gluten that is found in wheat and other grains. Vitamin D is a prohormone with a number of biochemical functions including immunomodulatory functions in its active form. Supplementation with large doses of vitamin D induces symptoms that are similar to celiac disease in some of the population. Some researchers have noted that consumption of large doses of oral vitamin D early in life is associated with increased incidence of allergic diseases later in life. An examination of celiac disease suggests that an allergy is fundamental to its development and it features Th2 cytokine elevations which typically characterize allergic diseases. In addition it has comorbidity with allergic diseases where exposure to large doses of vitamin D early in life is a risk factor. This raises the possibility that large doses of vitamin D early in life could be a risk factor for inducing celiac disease later in life as well. The comorbidity between Williams syndrome, which is characterized by spikes in blood levels of vitamin D, and celiac disease gives additional credence to this hypothesis. Epidemiological evidence supports this hypothesis as well. Vitamin D consumption among the young and celiac disease prevalence are high in Sweden, Finland, and the United States. Vitamin D consumption among the young and celiac disease prevalence are low in Russia and Germany. The timing of the increases in prevalence in the United States and Sweden also coincides with increasing vitamin D consumption. This is most striking in Sweden where a law required significant vitamin D fortification of food starting in 1983 and the start of the celiac epidemic in Sweden has been independently dated from 1984. This hypothesis also provides a potential explanation for some seemingly contradictory results in the literature regarding breastfeeding and risk of celiac disease.

Risk Factors for Celiac Disease: Genetics vs Environment

Risk Factors for Celiac Disease: Genetics vs Environment

Association of maternal education, early infections, and antibiotic use with celiac disease: a population-based birth cohort study in northeastern Italy.

We conducted a population-based birth cohort study of approximately 203,000 babies born in northeastern Italy (1989-2012) to investigate perinatal variables, early infections leading to hospital admission, and antibiotic use in the first 12 months of life as possible risk factors for celiac disease (CD). Incident CD cases were identified from pathology reports, hospital discharge records, and exemptions from prescription charges for clinical tests. Multivariate Poisson regression models were fitted to estimate incidence rate ratios (IRRs). A total of 1,227 children had CD; CD was histopathologically confirmed in 866 (71%). Female sex, maternal age, and high maternal educational level were found to be significantly associated with CD. Gastrointestinal infections were strongly associated with a subsequent diagnosis of CD (IRR = 2.04, 95% confidence interval (CI): 1.30, 3.22). Antibiotic use was significantly associated with CD onset (IRR = 1.24, 95% CI: 1.07, 1.43), with a dose-response relationship for number of courses (P-trend < 0.01). Cephalosporin use strongly increased the risk of CD (IRR = 1.42, 95% CI: 1.18, 1.73). Use of antibiotics (supported by the dose-response relationship) and gastrointestinal infections in the first year of life may facilitate the early onset of CD by altering intestinal microflora and the gut mucosal barrier. Perinatal factors, including cesarean section, had little influence on the risk of childhood CD.

In depth analysis of risk factors for coeliac disease amongst children under 18 years old in the Gaza strip. A cross sectional study.

Coeliac disease is an important clinical disorder affecting the human gastrointestinal tract leading to multiple signs and symptoms in different body organs. This disease was the subject of a cross sectional descriptive-analytic study conducted in the Gaza Strip during 2010. Objectives were oriented to identify and verify several variables and attributes affecting the prognosis of coeliac disease in the patients. Ninety five children out of 113 patients were arranged into two groups according to age from 2 to 11 years and from 12 to 18 years old. Results showed the poor interest of health professionals regarding coeliac disease in the Gaza Strip. The mean age of study population was 5.47 years for males and 8.93 years for females. The lifestyle of coeliac patients was directly proportional with better nutritional indictors. Poor recognition of the emblem illustrating gluten in foods implicates effective health awareness or promotion. The more knowledgeable patients or mothers (P = 0.036) were the more compliant. The compliance to giving gluten free foods outside home was statistically significant (P = 0.037). Similarly, cautious approach when buying foods or detergents (P = 0.011). According to BMI 74.4%, 23.4% and 3.2% of all patients were normal, underweight and overweight respectively. Albumin blood level was normal in 32.6% and low in 67.4%. Meanwhile, blood calcium level was normal in 76.8%, low in 21.1% and high in 2.1% of all patients. Conclusion: The study showed that recreation and social activities for coeliac patients are substantially missing in the Gaza Strip. Moreover, the study proved that AEI is a reliable centre for care of coeliac disease patients and conducting relevant studies. Recommendation: There is a need for thorough and continuous community and institutional mobilization regarding coeliac disease in the Gaza Strip and in Palestine.

Early Vaccinations Are Not Risk Factors for Celiac Disease

To investigate if changes in the national Swedish vaccination program coincided with changes in the celiac disease (CD) incidence rate in infants (ie, the Swedish CD Epidemic), and to assess the potential association between these vaccinations and CD risk. All studies were based on the National Swedish Childhood Celiac Disease Register. Using an ecological approach, we plotted changes over time in the national vaccination program in the graph displaying CD incidence rate. A population-based incident case-referent study of invited infants was performed. Exposure information was received through a questionnaire and child health clinic records. Vaccines explored were diphtheria/tetanus, pertussis (acellular), polio (inactivated), Haemophilus influenzae type b (conjugated), measles/mumps/rubella, and live attenuated bacillus Calmette-Guérin (BCG) in children with increased tuberculosis risk. Findings were subjected to a birth cohort analysis. Introduction of pertussis vaccine coincided in time with decreasing CD incidence rates. In the infant case-referent study, however, neither vaccination against pertussis (odds ratio 0.91; 95% confidence interval 0.60-1.4), nor against Haemophilus influenzae type b or measles/mumps/rubella was associated with CD. Coverage for the diphtheria/tetanus and polio vaccines was 99%. BCG was associated with reduced risk for CD (adjusted odds ratio 0.54; 95% confidence interval 0.31-0.94). Discontinuation of general BCG vaccination did not affect the cumulative incidence of CD at age 15 years. Early vaccinations within the national Swedish program were not associated with CD risk, nor could changes in the program explain the Swedish epidemic. A protective effect by BCG was suggested, which could be subject to further studies.

Early Vaccinations Are Not Risk Factors for Celiac Disease

Early Vaccinations Are Not Risk Factors for Celiac Disease

Cryptic fate of gliadin epitopes: implication for celiac disease (P730) (106.26)

Abstract Epitopes of an intact antigen that elicit potent T cell activation are classified as immunodominant epitopes. By contrast, epitopes that fail to trigger a T cell response, but can bind to class II, are called cryptic epitopes. HLA-DM (DM), an important regulator of antigen presentation, determines the immunodominant and cryptic fate of epitopes. Notably, however, we previously reported that DM interacts weakly with HLA-DQ2 (DQ2), a genetic risk factor for celiac disease (CD). Here, using the T x B hybrid cell line, T2, transfected with DQ2 with or without higher than physiological levels of DM, we have investigated the contribution of DM in the presentation of different gliadin epitopes (VII). The presentation of digested gluten requires internal processing and was dramatically inhibited when APCs were fixed. Cells lacking DM efficiently presented all four epitopes to gliadin-specific T cells. Interestingly, cells expressing DM were significantly compromised in their ability to display the above epitopes despite the higher level of surface DQ2 in DM+ cells. We conclude that all fourgliadin peptides were DM-suppressed epitopes. We hypothesize that in vivo the inefficient interaction between DQ2 and DM influences the fate of these epitopes, changing them from cryptic to immunodominant, and inducing a gliadin-specific immune response in CD patients expressing the DQ2 allele.

The prevalence and risk factors for coeliac disease among children and adolescents with type 1 diabetes mellitus

Aims Our aim was to determine in children with T1DM the prevalence of positive antibodies against tissue transglutaminase (anti-tTG IgA) as indices of coeliac disease (CD), as well as its clinical presentation, its determinants and its association with thyroid (anti-TG, anti-TPO) and pancreatic b-cell autoimmunity (anti-GAD). Methods The study included 105 children and adolescents with T1DM, aged (mean ± SD) 12.44 ± 4.76 years, with a T1DM duration of 4.41 ± 3.70 years. Results Fifty of our patients (47.6%) were positive for anti-GAD, 9/105 (8.6%) for anti-tTG IgA and 21/105(20%) for anti-thyroid antibodies. The anti-tTG IgA (+) children, in comparison with the rest of the study population, were of younger age (9.31 vs. 12.74 years, p = 0.038), shorter diabetes duration (2.16 vs. 4.62 years, p = 0.056) and had mild growth impairment (height SDS: −0.55 vs. +0.20, p = 0.055). Univariate logistic regression analysis revealed that the presence of anti-tTG IgA (+) was associated with younger age and shorter T1DM duration. Only 5/9 (55.6%) children with high titres of anti-tTG IgA developed mild gastrointestinal symptoms or growth retardation and had histological findings typical of CD. Conclusions The prevalence of anti-tTG IgA positivity among T1DM children was 8.6% and its occurrence was associated with younger age and short diabetes duration. Since CD presents in T1DM patients asymptomatically or with non-specific symptoms, periodic autoantibody screening is necessary for its early diagnosis.

Cystic fibrosis is a risk factor for celiac disease.

The coexistence of cystic fibrosis (CF) and celiac disease (CD) has been reported. To our knowledge there is no study directly comparing the incidence of CD in CF patients to that in the general population at the same time. There is no published data on genetic predisposition to CD in CF patients either. Therefore, in the present study we aimed to assess the genetic predisposition to CD and its incidence in CF patients comparing it to data from the general population. Two hundred eighty-two CF patients were enrolled in the study. In 230 CF patients the genetic predisposition to CD (the presence of HLA-DQ2/ DQ8) was assessed. In all CF patients, serological screening for CD was conducted. In patients with positive antiendomysial antibodies (EMA) gastroduenoscopy was offered. Intestinal histology was classified according to modified Marsh criteria. The results of serological CD screening in 3235 Polish schoolchildren and HLA-DQ typing in 200 healthy subjects (HS) were used for comparison. Positive EMA was found in 2.84% of the studied CF patients. The incidence of proven CD was 2.13%. The incidence of CD as well as positive serological screening were significantly more frequent in the CF group than in the general population. The frequency of CD-related HLA-DQ alleles in CF and HS did not differ. Genetic predisposition to celiac disease in cystic fibrosis patients is similar to that of the general population. However, our results suggest that cystic fibrosis is a risk factor for celiac disease development.

Non‐axial bone fracture but not depression as a risk factor for coeliac disease

Screening for coeliac disease is confined to subgroups at greater risk for the disease, including type 1 diabetes mellitus, autoimmune thyroid disease and family members of affected individuals. This study examined the hypothesis that patients taking antidepressants or presenting with fractures could represent new subgroups at higher risk for coeliac disease. A total of 105 and 199 consecutive patients presenting to hospital taking antidepressants and/or with a fracture was screened with IgA tissue transglutaminase and had their IgA serum levels quantified. Patients with positive serology were offered further diagnostic and management follow up. No patients taking antidepressants had positive serology. Seven with fractures had elevated titres of IgA tissue transglutaminase. All of these patients had presented with non-axial fractures, representing a prevalence of 5.2% (95% confidence interval: 1.4-8.9%). Uptake of further investigation and management was poor. Patients presenting with non-axial fractures may be a subgroup in whom coeliac screening may be indicated. There needs to be greater awareness of atypical presentations of coeliac disease.

Risk factors in familial forms of celiac disease.

Celiac disease has been reported in up to 2% of some European populations. A similar risk has been identified in the America and Australia where immigration of Europeans has occurred. Moreover, an increasing number of celiac disease patients are being identified in many Asian countries, including China and India. Finally, celiac disease has also been detected in Asian immigrants and their descendants to other countries, such as Canada. Within these so-called "general" celiac populations, however, there are specific high risk groups that have an even higher prevalence of celiac disease. Indeed, the single most important risk factor for celiac disease is having a first-degree relative with already-defined celiac disease, particularly a sibling. A rate up to 20% or more has been noted. Risk is even greater if a specific family has 2 siblings affected, particularly if a male carries the human leukocyte antigen-DQ2. Both structural changes in the small bowel architecture occur along with functional changes in permeability, even in asymptomatic first-degree relatives. Even if celiac disease is not evident, the risk of other autoimmune disorders seems significantly increased in first-degree relatives as well as intestinal lymphoma. Identification of celiac disease is important since recent long-term studies have shown that the mortality of celiac disease is increased, if it is unrecognized and untreated.

Fine mapping of the CELIAC2 locus on chromosome 5q31‐q33 in the Finnish and Hungarian populations

Celiac disease is a chronic inflammation of the small intestine, arising in genetically predisposed individuals as a result of ingestion of dietary gluten. The only confirmed and functionally characterised genetic risk factors for celiac disease are the DQ2 or DQ8 heterodimers at the major histocompatibility complex (MHC) class II locus (CELIAC1). These genes are necessary but alone not sufficient for disease onset. Genome-wide linkage scans have suggested chromosome 5q31-q33 (CELIAC2) as an important risk locus for celiac disease. This region has also been associated to other inflammatory disorders, although as yet, no clear gene associations have been found. In the current study, 11 celiac disease candidate loci were screened for genetic linkage in the Hungarian population. As the CELIAC2 locus showed the strongest evidence for linkage, this locus was selected for follow-up. Seventeen candidate genes were selected from the CELIAC2 locus, and genotyped using 48 haplotype tagging single nucleotide polymorphisms (SNPs) in large Finnish and Hungarian family materials. A subset of these, 40 tagging SNPs in 15 genes, were genotyped in an independent set of Finnish and Hungarian cases and controls. We confirmed linkage of this region with celiac disease and report strong linkage in both the Finnish and Hungarian populations. The association analysis showed modest associations throughout the whole region. These association findings were not replicated in the case-control datasets. Our study strongly supports the role of the CELIAC2 locus in celiac disease, but it also highlights the need for a more powerful study design in the region, to locate the true disease risk variants.

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...