Risk Factors For Celiac Disease Research Articles

Pervasive findings of directional selection realize the promise of ancient DNA to elucidate human adaptation.

We present a method for detecting evidence of natural selection in ancient DNA time-series data that leverages an opportunity not utilized in previous scans: testing for a consistent trend in allele frequency change over time. By applying this to 8433 West Eurasians who lived over the past 14000 years and 6510 contemporary people, we find an order of magnitude more genome-wide significant signals than previous studies: 347 independent loci with >99% probability of selection. Previous work showed that classic hard sweeps driving advantageous mutations to fixation have been rare over the broad span of human evolution, but in the last ten millennia, many hundreds of alleles have been affected by strong directional selection. Discoveries include an increase from ∼0% to ∼20% in 4000 years for the major risk factor for celiac disease at HLA-DQB1 ; a rise from ∼0% to ∼8% in 6000 years of blood type B; and fluctuating selection at the TYK2 tuberculosis risk allele rising from ∼2% to ∼9% from ∼5500 to ∼3000 years ago before dropping to ∼3%. We identify instances of coordinated selection on alleles affecting the same trait, with the polygenic score today predictive of body fat percentage decreasing by around a standard deviation over ten millennia, consistent with the "Thrifty Gene" hypothesis that a genetic predisposition to store energy during food scarcity became disadvantageous after farming. We also identify selection for combinations of alleles that are today associated with lighter skin color, lower risk for schizophrenia and bipolar disease, slower health decline, and increased measures related to cognitive performance (scores on intelligence tests, household income, and years of schooling). These traits are measured in modern industrialized societies, so what phenotypes were adaptive in the past is unclear. We estimate selection coefficients at 9.9 million variants, enabling study of how Darwinian forces couple to allelic effects and shape the genetic architecture of complex traits.

Elucidating the non-genetic risk factors for celiac disease: an umbrella review of meta-analyses.

The breadth and validity of the associations of nongenetic risk factors with celiac disease (CeD) are elusive in the literature. We aimed to evaluate which of these associations have strong epidemiological credibility and assessed presence and extent of potential literature biases. We systematically searched PubMed until April 2024 for systematic reviews and meta-analyses of studies examining associations between putative risk factors and CeD. Each association was categorized in five evidence grades (convincing, highly suggestive, suggestive, weak, and not statistically significant) based on broadly used criteria for evaluating quality of evidence in observational studies. Five eligible publications were included, describing 15 meta-analytic associations on seven nongenetic risk factors, three of which were nominally significant ( P < 0.05). None of the associations received a strοng or highly suggestive evidence. One meta-analytic association received suggestive evidence, namely any infections during childhood and adulthood for a higher risk of CeD (OR, 1.37; 95% CI, 1.2-1.56; P =3.77 × 10 -6 ). Two meta-analyses reported weak evidence, pertaining to current smoking for a lower risk of CeD (OR, 0.52; 95% CI, 0.32-0.84; P =7.84 × 10 -3 ) and use of antibiotics for a higher risk (OR, 1.2; 95% CI, 1.04-1.38; P 14.8 × 10 -3 ). The rest of the meta-analyses did not report statistically significant results, and pertained to breastfeeding, time of gluten introduction, rotavirus vaccination, and cesarean section. No association of nongenetic risk factors for CeD received high levels of evidence. The evidence was suggestive for the association of any infections during childhood and adulthood with higher risk of CeD. More and prospective future research is warranted.

Associations between Celiac Disease, Extra-Gastrointestinal Manifestations, and Gluten-Free Diet: A Narrative Overview.

Millions of children and adults worldwide suffer from undiagnosed and untreated celiac disease (CeD). The clinical picture of CeD is highly heterogeneous and comprises manifestations that can affect almost the whole body. This narrative overview is aimed at characterizing diseases and complaints that are associated with unrecognized CeD and that frequently involve sites other than the gastrointestinal (G.I.) tract, i.e., dental, otorhinolaryngological, and ocular complications; skin and hair abnormalities; afflictions of the bones, joints, and muscles; cardiovascular affectations; kidney diseases; neuro-psychiatric disorders; and gynecological-obstetrical manifestations. The association between CeD and extra-GI manifestations is frequently overlooked, which leads to a delay in diagnosis. Most CeD-mediated disorders can be treated with a strict gluten-free diet (GFD), but some of them are irreversible unless CeD is diagnosed in time. Some manifestations can be classified as risk factors for CeD, and CeD screening tests for affected patients should be selectively considered. Apart from gastroenterologists, specialists in other medical disciplines can play an important role in identifying people with unrecognized CeD and may help prevent its progress and long-term complications. Further comprehensive investigations are necessary to clarify the pathogenesis of extra-GI manifestations and the effect of a GFD.

A case-control epidemiological survey on potential risk factors for celiac disease.

Celiac disease (CD) is a chronic autoimmune disorder caused by a complex interplay between genetic and environmental factors. The main goal of our case-control study was to analyse the association of environmental factors with the odds of CD development in a sample of the Slovak population. Data were collected from 1,226 respondents (534 CD patients and 692 controls) by a questionnaire. The impact of analysed parameters on the chance of disease development was assessed by multiple regression analysis and expressed as odds ratios (OR). Values of p < 0.05 were considered statistically significant. In the patient group, celiac disease was significantly more prevalent in women than in men (OR = 1.52, p = 0.010). Respondents with a positive family history of CD showed 2.9-fold higher odds of CD compared to others (p < 0.001), and respondents with coexisting autoimmune diseases had 2.6-fold higher odds of CD (p < 0.001). Subjects who had taken antibiotics at least three times a year during childhood had 1.95-fold higher odds of developing CD compared to those who took them less frequently or not at all (p = 0.022). Conversely, individuals who were breastfed in infancy had lower odds of CD compared to non-breastfed respondents (OR = 0.53, p < 0.001). The mode of delivery (vaginal vs. caesarean section), overcoming severe infections, and the timing of gluten introduction in childhood did not show a statistically significant effect on the odds of developing CD. Based on our data, being female, having a positive family history of CD, suffering from another autoimmune disease, and frequent use of antibiotics are factors associated with an increased chance of developing CD. On the other hand, breastfeeding in infancy seems to have a protective effect. Our findings highlight the importance of further research in understanding the complexities of this autoimmune condition and providing a foundation for prevention strategies.

Investigating the role of iron status in the development of coeliac disease: a Mendelian randomisation study

ObjectiveThe environmental trigger behind the increasing prevalence of coeliac disease is not known. One suggested cause is iron deficiency, which is common in coeliac disease. We aimed to evaluate this...

S1536 Iron Deficiency and the Development of Celiac Disease

Introduction: The prevalence of celiac disease is increasing; however, the cause for this increase is unknown. Iron deficiency is one suggested environmental trigger for celiac disease development. We aimed to evaluate this possible association through the use of Mendelian randomization (MR). MR capitalizes on the random allocation of single nucleotide polymorphisms (SNPs) at conception, and under certain assumptions can suggest causality. Methods: We conducted a 2-sample MR study examining the relationship between SNPs associated with iron status and the presence of celiac disease. The SNPs were drawn from a meta-analysis of 3 genome-wide association studies (GWAS). The GWAS summary statistics from the UK Biobank, consisting of 336,638 White British individuals of whom 1,855 participants had celiac disease, were used to assess the association between these SNPs and celiac disease. The assumptions of MR were tested to evaluate for possible causality. We also performed an MR Egger test for pleiotropy. Results: There are 4 SNPs strongly associated with systemic iron status. Using PhenoScanner, we found that these SNPs were not significantly associated with known risk factors for celiac disease. All 4 were available in the UK Biobank summary statistics, and utilizing these SNPs, we harmonized exposure and outcome associations. We found that higher iron status was negatively associated with risk of celiac disease (odds ratio per 1 standard deviation increase in serum iron: 0.65, 95% CI 0.47-0.91). We performed leave-one-out analyses and had consistent results and did not find one single variant to be driving this association. All 3 assumptions of MR appeared plausible. Conclusion: We found that genetically lower iron levels were associated with an increased risk of having celiac disease. If the assumptions of MR hold, this association suggests a causal role of iron deficiency in celiac disease development. While unlikely to be the only environmental trigger, iron deficiency is prevalent in both the general and celiac population. One possible mechanism for this pathogenic role is that the transferrin receptor 1, which is upregulated in the setting of iron deficiency, directly transports gliadin peptides across enterocytes – a key step in celiac disease development. Our findings highlight a potential opportunity for celiac disease prevention.

Presence of high‐risk HLA genotype is the most important individual risk factor for coeliac disease among at‐risk relatives

Family screening has been advocated as a means to reduce the major underdiagnosis of coeliac disease. However, the precise risk of the disease in relatives and the impact of patient- and relative-related individual factors remain obscure. To investigate the individual risk of coeliac disease among patients' relatives. Altogether 2943 relatives of 624 index patients were assessed for the presence of previous coeliac disease diagnosis, or were screened for the disease. Coeliac disease-associated human leucocyte antigen (HLA) genotype was determined from all participants. The association between individual factors and new screening positivity was assessed by logistic regression. There were 229 previously diagnosed non-index relatives with coeliac disease and 2714 non-affected (2067 first-degree, 647 more distant) relatives. Of these 2714 relatives, 129 (4.8%) were screening-positive (first-degree 5.1%, second-degree 3.6%, more distant 3.5%). The combined prevalence of the previously diagnosed and now detected cases in relatives was 12.2% (6.3% clinically detected, 5.9% screen-detected). In univariate analysis, age <18years at diagnosis (odds ratio 1.60, 95% CI 1.04-2.45) in index, and age 41-60years (1.73, 1.10-2.73), being a sibling (1.65, 1.06-2.59) and having the high-risk genotype (3.22, 2.01-5.15 DQ2.5/2.5 or DQ2.5/2.2 vs other risk alleles) in relatives were associated with screening positivity. Only high-risk HLA remained significant (2.94, 1.80-4.78) in multivariable analysis. Unrecognised coeliac disease was common among at-risk relatives even in a country with an active case-finding policy, and also in relatives more distant than first-degree. The presence of a high-risk genotype was the most important predictor for screening positivity. ClinicalTrials.gov identifier NCT03136731.

Paediatric rotavirus vaccination, coeliac disease and type 1 diabetes in children: a population-based cohort study

BackgroundRotavirus infection has been proposed as a risk factor for coeliac disease (CD) and type 1 diabetes (T1D). The UK introduced infant rotavirus vaccination in 2013. We have previously shown that rotavirus vaccination can have beneficial off-target effects on syndromes, such as hospitalised seizures. We therefore investigated whether rotavirus vaccination prevents CD and T1D in the UK.MethodsA cohort study of children born between 2010 and 2015 was conducted using primary care records from the Clinical Practice Research Datalink. Children were followed up from 6 months to 7 years old, with censoring for outcome, death or leaving the practice. CD was defined as diagnosis of CD or the prescription of gluten-free goods. T1D was defined as a T1D diagnosis. The exposure was rotavirus vaccination, defined as one or more doses. Mixed-effects Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CIs). Models were adjusted for potential confounders and included random intercepts for general practices.ResultsThere were 880,629 children in the cohort (48.8% female). A total of 343,113 (39.0%) participants received rotavirus vaccine; among those born after the introduction of rotavirus vaccination, 93.4% were vaccinated. Study participants contributed 4,388,355 person-years, with median follow-up 5.66 person-years. There were 1657 CD cases, an incidence of 38.0 cases per 100,000 person-years. Compared with unvaccinated children, the adjusted HR for a CD was 1.05 (95% CI 0.86–1.28) for vaccinated children. Females had a 40% higher hazard than males. T1D was recorded for 733 participants, an incidence of 17.1 cases per 100,000 person-years. In adjusted analysis, rotavirus vaccination was not associated with risk of T1D (HR = 0.89, 95% CI 0.68–1.19).ConclusionsRotavirus vaccination has reduced diarrhoeal disease morbidity and mortality substantial since licencing in 2006. Our finding from this large cohort study did not provide evidence that rotavirus vaccination prevents CD or T1D, nor is it associated with increased risk, delivering further evidence of rotavirus vaccine safety.

Infections in early life as risk factor for coeliac disease

IntroductionAmong the environmental factors that can affect the pathological response to gluten in coeliac disease (CD), the factors that influence the immune response, such as infections and use of antibiotics, are proposed. Our objective is to determine the relationship between infections in early life and the risk of CD. Patients and methodsA retrospective case-control study, including patients aged 0–16 years with a diagnosis of CD was performed between the years 2014–2018. An analysis was made of documented infections in the first 6 months of life, types of infection (respiratory, gastrointestinal, urinary, others), microorganisms involved, and antibiotic therapy used. ResultsA total of 93 coeliac patients, 93 controls, and 237 infectious episodes were registered. Documented infections affected 67.7% of coeliac patients and 50.5% of controls (P=.017), with a mean of 1.49±1.53 episodes in the coeliac group and 1.05±1.5 in the controls (P=.016). Documented infections in the first 6 months of life doubles the risk of developing CD (OR 2.05; 95% CI; 1.13–3.73), with this risk being higher for respiratory infections, which multiply the risk by 2.3 (OR 2.30, 95% CI; 1.28–4.14). Also, having 3 or more respiratory infections in the first 6 months of life multiplied the risk by 2.8 (OR 2.79, 95% CI; 1.03–7.54). No differences were found related to the types of involved microorganism or regarding the use of antibiotics. ConclusionsInfections in the first 6 months of life increase the risk of developing CD, especially for respiratory infections and, to a greater extent, if 3 or more episodes occur. The use of antibiotics in this period of life has not been related to an increased risk of CD.

Paediatric Rotavirus Vaccination, Coeliac Disease and Type 1 Diabetes in Children: A Population-Based Cohort Study

Background: Rotavirus infection has been proposed as a risk factor for coeliac disease (CD) and type 1 diabetes (T1D). The UK introduced infant rotavirus vaccination in 2013. We therefore investigated whether rotavirus vaccination prevents CD and T1D in the UK. Methods: A cohort study of children born between 2010 and 2015 was conducted using primary care records from the Clinical Practice Research Datalink. Children were followed-up from three months to seven years old, with censoring for outcome, death or leaving the practice. CD was defined as diagnosis of CD or the prescription of gluten-free goods. T1D was defined as a T1D diagnosis. The exposure was rotavirus vaccination, defined as one or more doses. Mixed-effects Cox regression was used to estimate Hazard ratios (HR) and 95% confidence intervals (CIs). Models were adjusted for potential confounders and included random intercepts for general practices. Findings: There were 880 629 children in the cohort (48·8% female). A total of 343 113 (39·0%) participants received rotavirus vaccine; among those born after the introduction of rotavirus vaccination, 93·4% were vaccinated. Study participants contributed 4 526 794 person-years, with median follow-up 5·85 person-years. There were 1 657 CD cases, an incidence of 36·6 cases per 100 000 person-years. Compared with unvaccinated children the adjusted HR for a CD was 1·03 (95% CI 0·84-1·26) for vaccinated children. Females had a 40% higher hazard than males. T1D was recorded for 733 participants, an incidence of 16·2 cases per 100 000 person-years. In adjusted analysis rotavirus vaccination was not associated with risk of T1D (HR 0·9, 95% CI 0·69-1·20). Interpretation: This study did not provide evidence that rotavirus vaccination prevents CD or T1D, nor is it associated with increased risk, delivering further evidence of rotavirus vaccine safety. Funding: This study is funded by the National Institute for Health Research. Declaration of Interests: DH and MIG report grants on the topic of rotavirus vaccines, outside of the submitted work, from GlaxoSmithKline Biologicals, Sanofi Pasteur and Merck and Co (Kenilworth, New Jersey, US) after the closure of Sanofi Pasteur-MSD in December 2016. MIG also reports personal fees for consultancy, outside the submitted work, from GlaxoSmithKline Biologicals. TI and KF have nothing to disclose. Ethics Approval Statement: Ethical approval for this research was given by the Independent Scientific and Ethical Committee (ISAC) of the CPRD (reference 20_024RA2). CPRD obtains annual rolling ethical approval (reference number 05/MRE04/87) and no additional ethical approval was required for this project which meets ISAC requirements.

Elevated Levels of 1,25-Dihydroxyvitamin D in Plasma as a Missing Risk Factor for Celiac Disease.

The prevalence of celiac disease (CD) has increased significantly in some developed countries in recent decades. Potential risk factors that have been considered in the literature do not appear to provide a convincing explanation for this increase. This has led some researchers to hypothesize that there is a “missing environmental factor” that increases the risk of CD. Based on evidence from the literature, the author proposes that elevation in plasma levels of 1,25-dihydroxyvitamin D [1,25(OH)2D] is a missing risk factor for CD, and relatedly that significant oral vitamin D exposure is a “missing environmental factor” for CD. First, elevated plasma levels of 1,25(OH)2D are common in CD, especially in the newly diagnosed. Second, nine distinct conditions that increase plasma levels of 1,25(OH)2D are either associated with CD or have indications of such an association in the literature. Third, a retrospective study shows that sustained oral vitamin D supplementation in infancy is associated with increased CD risk, and other studies on comorbid conditions support this association. Fourth, large doses of oral vitamin D upregulate many of the same cytokines, chemokines, and toll-like receptors that are upregulated in CD. Fifth, epidemiological evidence, such as the timing of the inception of a CD “epidemic” in Sweden, the increased prevalence of CD in Finland and the United States in recent decades, the unusually low prevalence of CD in Germany, and the differential in prevalence between Finnish Karelians and Russian Karelians, may all be explained by oral vitamin D exposure increasing CD risk. The same is true of some seemingly contradictory results in the literature on the effects of breastfeeding on CD risk. If future research validates this hypothesis, adjustments to oral vitamin D consumption among those who have genetic susceptibility may decrease the risk of CD in these individuals.

Association Between Antibiotics in the First Year of Life and Celiac Disease

The intestinal microbiota is believed to be involved in the pathogenesis of celiac disease, in addition to genetic variants and dietary gluten. The gut microbiota is strongly influenced by systemic antibiotics-especially in early life. We explored the association between exposure to a systemic antibiotic in the first year of life and risk of diagnosed celiac disease. We performed an observational nationwide register-based cohort study. We included all children born in Denmark from 1995 through 2012 or Norway from 2004 through 2012. Children born in Denmark were followed until May 8, 2015 (age at end of follow-up was 2.3-20.3 years) and children born in Norway were followed until December 31, 2013 (age at end of follow-up was 1-10 years). We collected medical information from more than 1.7 million children, including 3346 with a diagnosis of celiac disease. Exposure to systemic antibiotics was defined as a dispensed systemic antibiotic in the first year of life. Exposure to systemic antibiotics in the first year of life was positively associated with diagnosed celiac disease in the Danish and Norwegian cohorts (pooled odds ratio 1.26, 95% confidence interval 1.16-1.36). We found a dose-dependent relation between an increasing number of dispensed antibiotics and the risk of celiac disease (pooled odds ratio for each additional dispensed antibiotic 1.08, 95% confidence interval 1.05-1.11). No specific type of antibiotic or age period within the first year of life was prominent. Adjustment for hospital admissions with an infectious disease in the first year of life did not change the estimates; adjustment for the number of maternally reported infections in the child in 2 large sub-cohorts decreased the association slightly (pooled odds ratio 1.18, 95% confidence interval 0.98-1.39). In a nationwide study of children in Denmark and Norway, we found exposure to systemic antibiotics in the first year of life to be associated with a later diagnosis of celiac disease. These findings indicate that childhood exposure to systemic antibiotics could be a risk factor for celiac disease.

ASSOCIATION OF TNF- α-308G>A POLYMORPHISM WITH SUSCEPTIBILITY TO CELIAC DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS.

There is increasing evidence to show that TNF-α -308G>A polymorphism may be a risk factor for celiac disease, but the results are inconsistent. Thus, we aimed to perform a meta-analysis involving published studies up to January 2019 to elucidate the association. To assess the effect of TNF-α -308G>A polymorphism on celiac disease susceptibility, we searched PubMed, ISI Web of Knowledge, Chinese National Knowledge Infrastructure (CNKI) databases to identify eligible studies, without restriction. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the susceptibility to celiac disease. A total of 11 studies with 1147 cases and 1774 controls were selected for this meta-analysis. The pooled results indicated that TNF-α -308G>A polymorphism was associated with increased risk of celiac disease (A vs G: OR=2.077, 95% CI=1.468-2.939, P=≤0.001; AA vs GG: OR=8.512, 95% CI=3.740-19.373, P=≤0.001; AA+AG vs GG: OR=1.869, 95% CI=1.161-3.008, P=0.010; and AA+AG vs GG: OR=4.773, 95% CI=3.181-7.162, P≤0.001). Subgroup analysis by ethnicity also revealed significant association in Caucasians. In addition, there was a significant association between TNF-α -308G>A polymorphism and celiac disease risk in Italy, Spain and PCR-FRLP group studies. Our meta-analysis suggests that the TNF-α -308G>A polymorphism plays an important role in celiac disease susceptibility. However, our results are still needed to strengthen by further studies in different ethnicities and larger sample sizes.

Coeliac disease detection with an IgA/IgG-deamidated gliadin peptide based point of care test in community pharmacies

Background Coeliac disease affects 1% of the population, but 75% remain undiagnosed. Objective To conduct a case finding feasibility and efficacy study for the detection of coeliac disease in community pharmacies. Setting Six community pharmacies across Sheffield, UK. Method A prospective study was performed using a point of care test, Simtomax® (IgA/IgG-deamidated gliadin peptide) (C-test) in pharmacies. Pharmacy customers with symptoms suggestive of or risk factors for coeliac disease were tested with the C-test. Positive individuals were referred for a gastroscopy with duodenal biopsies alongside conventional serology. People with known coeliac disease, those on a gluten free diet or those who were investigated for coeliac disease were excluded. Main outcome measure The case detection rate and the uptake rate of the C-test and gastroscopies. Results Five-hundred participants fulfilled the inclusion criteria and were tested with the C-test (369 females, 73.8%; age range 18–87, median 49). The C-test uptake rate was 63%, and the positive rate was 7.2% (36/500). Twenty-seven positive participants (75%) underwent further investigations, confirming three new cases of coeliac disease (0.6%). Conclusion It was feasible to use the C-test as a case finding tool in pharmacies. There was good uptake for the C-test, although the case detection rate and the test specificity were low. Based on this, the C-test has a limited role in case finding in a community pharmacy setting.

Validation of a novel single-drop rapid human leukocyte antigen-DQ2/-DQ8 typing method to identify subjects susceptible to celiac disease.

Background and AimHuman leukocyte antigen (HLA)‐DQ2 and/or ‐DQ8 is an essential risk factor for celiac disease (CD). About 90–95% of patients with CD carry HLA‐DQ2/‐DQ8 alleles, and HLA‐DQ typing is considered an additional diagnostic test. Conventional polymerase chain reaction (PCR)‐based HLA‐DQ typing methods are expensive, complex, and a time‐consuming process. We assessed the efficacy of a novel HLA‐DQ typing method, “Celiac Gene Screen,” for the detection of CD‐associated HLA haplotypes.MethodsTo assess the diagnostic performance of the Celiac Gene Screen test, 100 ethylenediaminetetraacetic acid (EDTA) blood samples, already characterized by the conventional HLA‐DQ typing method, that is, PCR sequence‐specific oligonucleotide probes (PCR‐SSOP), a concordance between both the methods were explored. For validity, a further 300 EDTA blood samples with unknown HLA‐DQ status were genotyped using the Celiac Gene Screen test, including 141 samples from CD, 56 first‐degree relatives (FDRs) of CD and 103 samples from controls.ResultsOf the 100 samples with known status of HLA‐DQ alleles, 79 samples were HLA‐DQ2 and/or ‐DQ8 positive, and 21 samples were HLA‐DQ2 and/or ‐DQ8 negative by conventional PCR. These 100 samples were re‐typed using the Celiac Gene screen kit; all 79 positives were typed positive, and 21 negatives were typed negative for HLA‐DQ alleles. Among 300 samples with unknown HLA‐DQ status, 118 of 141 (84%) patients with CD, 48 of 56 (86%) FDRs of CD, and 52 of 103 (50%) controls typed positive for HLA‐DQ alleles.ConclusionsThe Celiac Gene Screen HLA‐DQ typing method showed excellent concordance with the conventional HLA‐DQ typing method and could be a cost‐reducing and effective method for CD‐associated HLA screening.

Who Should We Screen for Celiac Disease? Prevalence and Risk Factors for Celiac Disease in USA: A Large Population-Based Study of 83,090 Patients With Celiac Disease

Who Should We Screen for Celiac Disease? Prevalence and Risk Factors for Celiac Disease in USA: A Large Population-Based Study of 83,090 Patients With Celiac Disease

Avoidance of Cow's Milk–Based Formula for At-Risk Infants Does Not Reduce Development of Celiac Disease: A Randomized Controlled Trial

Feeding during the first months of life might affect risk for celiac disease. Individuals with celiac disease or type 1 diabetes have been reported to have high titers of antibodies against cow's milk proteins. Avoidance of cow's milk-based formula for infants with genetic susceptibility for type 1 diabetes reduced the cumulative incidence of diabetes-associated autoantibodies. We performed a randomized controlled trial in the same population to study whether weaning to an extensively hydrolyzed formula reduced the risk of celiac disease autoimmunity or celiac disease. We performed a double-blind controlled trial of 230 infants with HLA-defined predisposition to type 1 diabetes and at least 1 family member with type 1 diabetes. The infants were randomly assigned to groups fed a casein hydrolysate formula (n= 113) or a conventional formula (control, n= 117) whenever breast milk was not available during the first 6-8 months of life. Serum samples were collected over a median time period of 10 years and analyzed for antibodies to tissue transglutaminase (anti-TG2A) using a radiobinding assay, to endomysium using an immunofluorescence assay, and antibodies to a deamidated gliadine peptide using an immunofluorometry assay. Duodenal biopsies were collected if levels of anti-TG2A exceeded 20 relative units. Cow's milk antibodies were measured during the first 2 years of life. Of the 189 participants analyzed for anti-TG2A, 25 (13.2%) tested positive. Of the 230 study participants observed, 10 (4.3%) were diagnosed with celiac disease. We did not find any significant differences at the cumulative incidence of anti-TG2A positivity (hazard ratio, 1.14; 95% confidence interval, 0.51-2.54) or celiac disease (hazard ratio, 4.13; 95% confidence interval, 0.81-21.02) between the casein hydrolysate and cow's milk groups. Children who developed celiac disease had increased titers of cow's milk antibodies before the appearance of anti-TG2A or celiac disease. In a randomized controlled trial of 230 infants with genetic risk factors for celiac disease, we did not find evidence that weaning to a diet of extensively hydrolyzed formula compared with cow's milk-based formula would decrease the risk for celiac disease later in life. Increased titers of cow's milk antibody before anti-TG2A and celiac disease indicates that subjects with celiac disease might have increased intestinal permeability in early life. ClinicalTrials.gov Number: NCT00570102.

Extra Intestinal Manifestations of CD: Common Pathways in the Gut- remote Organs’ Axes

Genetic and environmental risk factors for celiac disease are well established, however, the precipitating events leading to development of celiac disease and associated conditions remain enigmatic. Being a multi-faced, multi-organ disease and the multiple extra intestinal phenotypes of celiac disease, further more add to its complexity. The present editorial summarizes the potential mechanisms connecting gut eco system events to remote organ manifestations and dysfunctions in celiac disease. It is suggested that nutrients, the microbiome/dysbiome interplay, the local post translational modification of naive proteins, the leaky gut and the leaked immunogenic or toxic molecules or complexes and the circulating pro-inflammatory immune cells and cytokines are at the basis of the gut-remote organ pathologies, in CD.

Dysbiosis a risk factor for celiac disease.

Celiac disease remains one of the most challenging pathologies of the small intestine. It involves multiple pathogenic pathways and there are no disease-changing pharmacological agents available against it yet. The term microbiota refers to the community of microorganisms that inhabit a particular region of the body. Normal gut microbiota has a vital role in maintaining the intestinal homeostasis and promoting health. Celiac disease is associated with microbiota alteration, especially with an increase in the number of Gram-negative bacteria and a decrease in the number of Gram-positive bacteria. There is a strong relationship between intestinal dysbiosis and celiac disease, and recent studies are aimed at determining whether the celiac disease is a risk factor for dysbiosis or dysbiosis is for celiac disease. Therefore, the aim of this review was to assess the latest findings regarding the gut microbiota and its impact on the celiac disease, including therapeutic aspects.

High Incidence of Celiac Disease in a Long-term Study of Adolescents With Susceptibility Genotypes

Little is known about the incidence of celiac disease in the general population of children in the United States. We aimed to estimate the cumulative incidence of celiac disease in adolescents born in the Denver metropolitan area. We collected data on HLA-DR, DQ genotypes of 31,766 infants, born from 1993 through 2004 at St. Joseph's Hospital in Denver, from the Diabetes Autoimmunity Study in the Young. Subjects with susceptibility genotypes for celiac disease and type 1 diabetes were followed up for up to 20 years for development of tissue transglutaminase autoantibodies (tTGA). Outcomes were the development of celiac disease autoimmunity (CDA) or celiac disease. CDA was defined as persistence of tTGA for at least 3 months or development of celiac disease. Celiac disease was defined based on detection of Marsh 2 or greater lesions in biopsy specimens or persistent high levels of tTGA. For each genotype, the cumulative incidence of CDA and celiac disease were determined. To estimate the cumulative incidence in the Denver general population, outcomes by each genotype were weighted according to the frequency of each of these genotypes in the general population. Of 1339 subjects followed up, 66 developed CDA and met criteria for celiac disease and 46 developed only CDA. Seropositivity for tTGA resolved spontaneously, without treatment, in 21 of the 46 subjects with only CDA (46%). The estimated cumulative incidence for CDA in the Denver general population at 5, 10, and 15 years of age was 2.4%, 4.3%, and 5.1%, respectively, and incidence values for celiac disease were 1.6%, 2.8%, and 3.1%, respectively. In a 20-year prospective study of 1339 children with genetic risk factors for celiac disease, we found the cumulative incidence of CDA and celiac disease to be high within the first 10 years. Although more than 5% of children may experience a period of CDA, not all children develop celiac disease or require gluten-free diets.