Risk Of Celiac Disease Autoimmunity Research Articles

Risk of celiac disease autoimmunity is modified by interactions between CD247 and environmental exposures

Season of birth, viral infections, HLA haplogenotypes and non-HLA variants are implicated in the development of celiac disease and celiac disease autoimmunity, suggesting a combined role of genes and environmental exposures. The aim of the study was to further decipher the biological pathways conveying the season of birth effect in celiac disease autoimmunity to gain novel insights into the early pathogenesis of celiac disease. Interactions between season of birth, genetics, and early-life environmental factors on the risk of celiac autoimmunity were investigated in the multicenter TEDDY birth cohort study. Altogether 6523 genetically predisposed children were enrolled to long-term follow-up with prospective sampling and data collection at six research centers in the USA, Germany, Sweden and Finland. Celiac disease autoimmunity was defined as positive tissue transglutaminase antibodies in two consecutive serum samples. There was a significant season of birth effect on the risk of celiac autoimmunity. The effect was dependent on polymorphisms in CD247 gene encoding for CD3ζ chain of TCR-CD3 complex. In particular, children with major alleles for SNP rs864537A > G, in CD247 (AA genotype) had an excess risk of celiac autoimmunity when born March–August as compared to other months. The interaction of CD247 with season of birth on autoimmunity risk was accompanied by interactions with febrile infections between the ages of 3–6 months. Considering the important role of TCR-CD3 complex in the adaptive immune response and our findings here, CD247 variants and their possible effect of subgroups in autoimmunity development could be of interest in the design of future gene-environment studies of celiac disease. ClinicalTrials.gov Identifier: NCT00279318.

Zonulin as a Biomarker for the Development of Celiac Disease.

Increased intestinal permeability seems to be a key factor in the pathogenesis of autoimmune diseases, including celiac disease (CeD). However, it is unknown whether increased permeability precedes CeD onset. This study's objective was to determine whether intestinal permeability is altered before celiac disease autoimmunity (CDA) in at-risk children. We also examined whether environmental factors impacted zonulin, a widely used marker of gut permeability. We evaluated 102 children in the CDGEMM study from 2014-2022. We included 51 CDA cases and matched controls, who were enrolled for 12 months or more and consumed gluten. We measured serum zonulin from age 12 months to time of CDA onset, and the corresponding time point in controls, and examined clinical factors of interest. We ran a mixed-effects longitudinal model with dependent variable zonulin. Children who developed CDA had a significant increase in zonulin in the 18.3 months (range 6-78) preceding CDA compared to those without CDA (slope differential = β = 0.1277, 95% CI: 0.001, 0.255). Among metadata considered, zonulin trajectory was only influenced by increasing number of antibiotic courses, which increased the slope of trajectory of zonulin over time in CDA subjects (P = .04). Zonulin levels significantly rise in the months that precede CDA diagnosis. Exposure to a greater number of antibiotic courses was associated with an increase in zonulin levels in CDA subjects. This suggests zonulin may be used as a biomarker for preclinical CeD screening in at-risk children, and multiple antibiotic courses may increase their risk of CDA by increasing zonulin levels.

Associations of dietary patterns between age 9 and 24 months with risk of celiac disease autoimmunity and celiac disease among children at increased risk

BackgroundHigher gluten intake in childhood is associated with increased incidence of celiac disease autoimmunity (CDA) and celiac disease. It remains to be studied whether different dietary patterns independent of gluten intake contribute to the incidence. ObjectivesThis study aimed to explore associations of dietary patterns by age 2 y with risk of CDA and celiac disease in genetically susceptible children. MethodsData was used from 6726 participants at genetic risk of type 1 diabetes and celiac disease enrolled in the observational cohort, The Environmental Determinants of Diabetes in the Young (TEDDY) study. Children were annually screened for tissue transglutaminase autoantibodies (tTGAs) from age 2 y. Principal component analysis extracted dietary patterns, based on intake of 27 food groups assessed by 3-d food records at age 9 to 24 mo. The primary outcome was CDA (i.e., persistently tTGA-positive in at least 2 consecutive samples), and the secondary outcome was celiac disease. During follow-up to mean age 11.0 (standard deviation 3.6) y, 1296 (19.3%) children developed CDA, and 529 (7.9%) were diagnosed with celiac disease. Associations of adherence to dietary patterns (per 5-unit increase) with the study outcomes were estimated by Cox regression models adjusted for risk factors including gluten intake. ResultsAt age 9 mo, a dietary pattern higher in the food groups vegetable fats and milk was associated with reduced risk of CDA (hazard ratio [HR]: 0.88; 95% confidence interval [CI]: 0.79, 0.98; P = 0.02). At 24 mo, a dietary pattern higher in the food groups wheat, vegetable fats, and juices, and lower in milk, meat, and oats at age 24 mo was associated with increased risk of CDA (HR: 1.18; 95% CI: 1.05, 1.33; P < 0.001) and celiac disease (HR: 1.24; 95% CI: 1.03, 1.50; P = 0.03). ConclusionsDietary patterns in early childhood are associated with risk of CDA and celiac disease in genetically predisposed children, independent of gluten intake.

Previous SARS-CoV-2 Infection Is Not Associated With Increased Celiac Disease Autoimmunity in Children and Adolescents.

Recent reports suggest severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections may increase the risk of celiac disease autoimmunity. This study aims to evaluate potential associations between coronavirus disease 2019 infection and tissue transglutaminase autoantibodies (TGA) immunoglobulin A. From 2020 to 2021, cross-sectional screening for SARS-CoV-2 antibodies and TGA was offered to 4,717 children in Colorado through the Autoimmunity Screening for Kids study. Multivariable logistic regression assessed association between previous SARS-CoV-2 infection and TGA positivity. Previous SARS-CoV-2 infection was not associated with TGA positivity (odds ratio 1.02, 95% confidence interval 0.63-1.59; P = 0.95). In this large-scale analysis, previous SARS-CoV-2 infection was not associated with celiac disease autoimmunity in Colorado children.

Maternal and neonatal viromes indicate the risk of offspring's gastrointestinal tract exposure to pathogenic viruses of vaginal origin during delivery.

A cumulative effect of enterovirus and gluten intake on the risk of celiac disease autoimmunity in infants highlights the significance of viral exposure in early life on the health of children. However, pathogenic viruses may be transmitted to the offspring in an earlier period, raising the possibility that women whose vaginas are inhabited by such viruses may have had their babies infected as early as the time of delivery. A high-resolution intergenerational virome atlas was obtained by metagenomic sequencing and virome analysis on 486 samples from six body sites of 99 mother-neonate pairs. We found that neonates had less diverse oral and enteric viruses than mothers. Vaginally delivered newborns seconds after birth had a more similar oral virome and more viruses of vaginal origin than cesarean-section (C-section) newborns (56.9% vs. 5.8%). Such viruses include both Lactobacillus phage and potentially pathogenic viruses, such as herpesvirus, vaccinia virus, and hepacivirus, illustrating a relatively high variety of the pioneer viral taxa at the time of delivery and a delivery-dependent mother-to-neonate transmission along the vaginal-oral-intestinal route. Neonates are exposed to vaginal viruses as they pass through the reproductive tract, and viruses of vaginal origin may threaten their health. These findings challenge the conventional notion that vaginal delivery is definitely better than cesarean delivery from the perspective of microbial transmission. Screening for vaginal virome before delivery is a worthwhile step to advocate in normal labor to eliminate the risk of intergenerational transmission of pathogenic viruses to offspring.

25(OH)D Levels in Infancy Is Associated With Celiac Disease Autoimmunity in At-Risk Children: A Case-Control Study.

Objectives: An observed variation in the risk of celiac disease, according to the season of birth, suggests that vitamin D may affect the development of the disease. The aim of this study was to investigate if vitamin D concentration is associated with the risk of celiac disease autoimmunity (CDA) in genetically at-risk children.Study Design: Children prospectively followed in the multinational The Environmental Determinants of Diabetes in the Young study, conducted at six centers in Europe and the US, were selected for a 1-to-3 nested case–control study. In total, 281 case–control sets were identified. CDA was defined as positivity for tissue transglutaminase autoantibodies (tTGA) on two or more consecutive visits. Vitamin D was measured as 25-hydroxyvitamin D [25(OH)D] concentrations in all plasma samples prior to, and including, the first tTGA positive visit. Conditional logistic regression was used to examine the association between 25(OH)D and risk of CDA.Results: No significant association was seen between 25(OH)D concentrations (per 5 nmol/L increase) and risk for CDA development during early infancy (odds ratio [OR] 0.99, 95% confidence interval [CI] 0.95–1.04) or childhood (OR 1.02, 95% CI 0.97–1.07). When categorizing 25(OH)D concentrations, there was an increased risk of CDA with 25(OH)D concentrations <30 nmol/L (OR 2.23, 95% CI 1.29, 3.84) and >75 nmol/L (OR 2.10, 95% CI 1.28–3.44) in early infancy, as compared with 50–75 nmol/L.Conclusion: This study indicates that 25(OH)D concentrations <30 nmol/L and >75 nmol/L during early infancy were associated with an increased risk of developing CDA in genetically at-risk children. The non-linear relationship raises the need for more studies on the possible role of 25(OH)D in the relation to celiac disease onset.

Association of Gluten Intake During the First 5 Years of Life With Incidence of Celiac Disease Autoimmunity and Celiac Disease Among Children at Increased Risk

To investigate if the amount of gluten intake during the first 5 years of life in genetically predisposed children is associated with increased risk of celiac disease autoimmunity and celiac disease.This prospective observational birth cohort study, The Environmental Determinants of Diabetes in the Young (TEDDY), followed children from birth up to 15 years of age at 6 clinical research centers in Finland, Sweden, Germany, and the United States. Between 2004 and 2010, 8676 newborns carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease were enrolled. Data on gluten intake were available in 6605 children (49% female) and this was the group included in the analysis. Median follow-up was 9.0 years (range, 1.0–13.0 years).Serum tissue transglutaminase (tTG) autoantibodies were measured annually in 6757 children from the age of 2 years. Gluten intake was estimated from 3-day food records collected at ages 6, 9, and 12 months and then biannually until 5 years old. Composite foods and recipes were broken down to ingredients. Absolute gluten intake (grams/day) was calculated.The primary outcome was celiac disease autoimmunity, defined as positive tTG autoantibodies found in 2 consecutive serum samples. Radiobinding assays were used to measure autoantibodies. In the US centers, IgA–tTG autoantibodies were measured. In the European centers, both IgA and IgG–tTG autoantibodies were measured. Diagnosis of celiac disease was confirmed by intestinal biopsy (Marsh score ≥2) or if a biopsy was not done, by persistently elevated tTG autoantibody levels (average of 2 yearly samples ≥ 100 U). Decision to perform endoscopy and biopsy was not determined by study protocol.1216 (18%) children developed celiac disease autoimmunity, and 447 (7%) developed celiac disease. The incidence for both outcomes peaked at 2 to 3 years of age. Children homozygous for HLA DR3-DQ2 were at the highest risk of celiac disease autoimmunity and celiac disease. Swedish residence, female sex, and family history of celiac disease were also associated with increased risk for both outcomes. The authors found that higher gluten intake during the first 5 years after birth was associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.30 [95% CI, 1.22–1.38]; absolute risk of 28.1% by the age of 3 years if a reference amount of gluten was consumed; absolute risk was 34.2% if the gluten amount consumed was 1-g/d higher than the reference amount. Similarly, the authors found that higher gluten intake during the first 5 years after birth was associated with an increased risk of celiac disease (hazard ratio, 1.50 [95% CI, 1.35–1.66]; absolute risk by the age of 3 years if the reference amount of gluten was consumed, 20.7%; absolute risk if the gluten amount consumed was 1-g/d higher than the reference amount, 27.9%. A post hoc analysis that focused on dietary gluten intake at the age of 2 years (just prior to the peak of celiac disease autoimmunity or celiac disease) found that daily gluten consumption of as little as 2 g (equivalent to 1 slice of bread) was associated with an increased risk of developing celiac disease autoimmunity or celiac disease; that risk was further increased for each gram of gluten ingested beyond this threshold.Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.In an accompanying editorial, it was pointed out that the amount of gluten ingested during the first 5 years after birth cannot completely explain the increased prevalence of celiac disease. Previous work examining the relationship between HLA genetics, gluten consumption, and celiac disease prevalence found no significant relationship between the amount of gluten ingested and the prevalence of celiac disease. As well, the prevalence of celiac disease in Finland is higher (1%–2.5%) than in Italy (0.7%–1.1%), yet infant wheat consumption in Italy is much higher than in Finland. Further investigation is needed, but pediatricians could consider counseling families of known genetic predisposition for celiac disease or type 1 diabetes to delay or diminish gluten ingestion in infants.

Association of Gluten Intake During the First 5 Years of Life With Incidence of Celiac Disease Autoimmunity and Celiac Disease Among Children at Increased Risk

High gluten intake during childhood may confer risk of celiac disease. To investigate if the amount of gluten intake is associated with celiac disease autoimmunity and celiac disease in genetically at-risk children. The participants in The Environmental Determinants of Diabetes in the Young (TEDDY), a prospective observational birth cohort study designed to identify environmental triggers of type 1 diabetes and celiac disease, were followed up at 6 clinical centers in Finland, Germany, Sweden, and the United States. Between 2004 and 2010, 8676 newborns carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease were enrolled. Screening for celiac disease with tissue transglutaminase autoantibodies was performed annually in 6757 children from the age of 2 years. Data on gluten intake were available in 6605 children (98%) by September 30, 2017. Gluten intake was estimated from 3-day food records collected at ages 6, 9, and 12 months and biannually thereafter until the age of 5 years. The primary outcome was celiac disease autoimmunity, defined as positive tissue transglutaminase autoantibodies found in 2 consecutive serum samples. The secondary outcome was celiac disease confirmed by intestinal biopsy or persistently high tissue transglutaminase autoantibody levels. Of the 6605 children (49% females; median follow-up: 9.0 years [interquartile range, 8.0-10.0 years]), 1216 (18%) developed celiac disease autoimmunity and 447 (7%) developed celiac disease. The incidence for both outcomes peaked at the age of 2 to 3 years. Daily gluten intake was associated with higher risk of celiac disease autoimmunity for every 1-g/d increase in gluten consumption (hazard ratio [HR], 1.30 [95% CI, 1.22-1.38]; absolute risk by the age of 3 years if the reference amount of gluten was consumed, 28.1%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 34.2%; absolute risk difference, 6.1% [95% CI, 4.5%-7.7%]). Daily gluten intake was associated with higher risk of celiac disease for every 1-g/d increase in gluten consumption (HR, 1.50 [95% CI, 1.35-1.66]; absolute risk by age of 3 years if the reference amount of gluten was consumed, 20.7%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 27.9%; absolute risk difference, 7.2% [95% CI, 6.1%-8.3%]). Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.

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.

Factors That Increase Risk of Celiac Disease Autoimmunity After a Gastrointestinal Infection in Early Life.

Little is known about the pathogenic mechanisms of gluten immunogenicity in patients with celiac disease. We studied temporal associations between infections and the development of celiac disease autoimmunity, and examined effects of HLA alleles, rotavirus vaccination status, and infant feeding. We monitored 6327 children in the United States and Europe carrying HLA risk genotypes for celiac disease from 1 to 4 years of age for presence of tissue transglutaminase autoantibodies (the definition of celiac disease autoimmunity), until March 31, 2015. Parental reports of gastrointestinal and respiratory infections were collected every third month from birth. We analyzed time-varying relationships among reported infections, rotavirus vaccination status, time to first introduction of gluten, breastfeeding, and risk of celiac disease autoimmunity using proportional hazard models. We identified 13,881 gastrointestinal infectious episodes (GIE) and 79,816 respiratory infectious episodes. During the follow-up period, 732 of 6327 (11.6%) children developed celiac disease autoimmunity. A GIE increased the risk of celiac disease autoimmunity within the following 3 months by 33% (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.11-1.59). This risk increased 2-fold among children born in winter and introduced to gluten before age 6 months (HR, 2.08; 95% CI, 1.46-2.98), and increased 10-fold among children without HLA-DQ2 alleles and breastfed for fewer than 4 months (HR, 9.76; 95% CI, 3.87-24.8). Risk of celiac disease autoimmunity was reduced in children vaccinated against rotavirus and introduced to gluten before age 6 months (HR, 0.57; 95% CI, 0.36-0.88). Gastrointestinal infections increase the risk of celiac disease autoimmunity in children with genetic susceptibility to this autoimmune disorder. The risk is modified by HLA genotype, infant gluten consumption, breastfeeding, and rotavirus vaccination, indicating complex interactions among infections, genetic factors, and diet in the etiology of celiac disease in early childhood.

Introduction of Gluten, HLA Status, and the Risk of Celiac Disease in Children

BackgroundThe relationship between the risk of celiac disease and both the age at which gluten is introduced to a child’s diet and a child’s early dietary pattern is unclear.MethodsWe randomly assigned 832 newborns who had a first-degree relative with celiac disease to the introduction of dietary gluten at 6 months (group A) or 12 months (group B). The HLA genotype was determined at 15 months of age, and serologic screening for celiac disease was evaluated at 15, 24, and 36 months and at 5, 8, and 10 years. Patients with positive serologic findings underwent intestinal biopsies. The primary outcome was the prevalence of celiac disease autoimmunity and of overt celiac disease among the children at 5 years of age.ResultsOf the 707 participants who remained in the trial at 36 months, 553 had a standard-risk or high-risk HLA genotype and completed the study. At 2 years of age, significantly higher proportions of children in group A than in group B had celiac disease autoimmunity (16% vs. 7%, P=0.002) and overt celiac disease (12% vs. 5%, P=0.01). At 5 years of age, the between-group differences were no longer significant for autoimmunity (21% in group A and 20% in group B, P=0.59) or overt disease (16% and 16%, P=0.78 by the log-rank test). At 10 years, the risk of celiac disease autoimmunity was far higher among children with high-risk HLA than among those with standard-risk HLA (38% vs. 19%, P=0.001), as was the risk of overt celiac disease (26% vs. 16%, P=0.05). Other variables, including breast-feeding, were not associated with the development of celiac disease.ConclusionsNeither the delayed introduction of gluten nor breast-feeding modified the risk of celiac disease among at-risk infants, although the later introduction of gluten was associated with a delayed onset of disease. A high-risk HLA genotype was an important predictor of disease. (Funded by the Fondazione Celiachia of the Italian Society for Celiac Disease; CELIPREV ClinicalTrials.gov number, NCT00639444.)

Risk of pediatric celiac disease according to HLA haplotype and country: evidence-based-medicine viewpoint.

This multi-centric cohort study [1] from four countries followed a group of infants with the HLA haplotype DR3-DQ2 or DR4-DQ8, from birth through the first few years of life; seeking the appearance of antibodies to tissue transglutaminase (tTG) (labeled as celiac disease autoimmunity), and development of celiac disease. This was part of a larger study evaluating the development of type 1 diabetes in a cohort of infants with genetic susceptibility (based on carrying the HLA haplotype DR3-DQ2 or DR4-DQ8) [2]. Over a median follow-up duration of nearly five years, the investigators reported 12% prevalence of celiac disease autoimmunity and 3% prevalence of celiac disease. They also identified that the respective risks of these two outcomes varied by the HLA genotype: 26% and 11% with homozygosity for DR3-DQ2 haplotype; 11% and 3% with DR3-DQ2/DR4-DQ8 haplotype; 8% and 3% with DR4-DQ8 homozygosity; and 3% and <1% among those with DR4-DQ8/DR8-DQ4 haplotype. There was statistically significant higher risk of celiac disease autoimmunity and celiac disease in infants from Europe (highest risk in Sweden), female gender, and those with family history of celiac disease.

Risk of Pediatric Celiac Disease According to HLA Haplotype and Country

BackgroundThe presence of HLA haplotype DR3–DQ2 or DR4–DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG).MethodsWe studied 6403 children with HLA haplotype DR3–DQ2 or DR4–DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies.ResultsThe median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3–DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3–DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4–DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25).ConclusionsChildren with the HLA haplotype DR3–DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries highlights the importance of studying environmental factors associated with celiac disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)

Risk of Celiac Disease Autoimmunity is Modified by Non-HLA Genetic Markers During the First Year of Clinical Type 1 Diabetes

Risk of Celiac Disease Autoimmunity is Modified by Non-HLA Genetic Markers During the First Year of Clinical Type 1 Diabetes

Risk of Celiac Disease Autoimmunity and Timing of Gluten Introduction in the Diet of Infants at Increased Risk of Disease

Risk of Celiac Disease Autoimmunity and Timing of Gluten Introduction in the Diet of Infants at Increased Risk of Disease

Rotavirus Infection Frequency and Risk of Celiac Disease Autoimmunity in Early Childhood: A Longitudinal Study

Few studies have assessed the role of specific gastrointestinal infections in celiac disease. We investigated whether increased frequency of rotavirus infection, a common cause of gastrointestinal infection and inflammation, predicts increased risk of celiac disease autoimmunity. A cohort of 1,931 children from the Denver metropolitan area who carried celiac disease human leukocyte antigen (HLA) risk alleles were followed from infancy for development of celiac disease autoimmunity, defined as positivity at two or more subsequent clinic visits for tissue transglutaminase (tTG) autoantibodies measured using a radioimmunoassay with human recombinant tTG. Blood samples were obtained at ages 9, 15, and 24 months, and annually thereafter. Rotavirus antibodies were assayed using an indirect enzyme immunoassay in serial serum samples from each case and two matched controls. Frequency of infections were estimated by the number of increases (> 2 assay coefficient of variation) in rotavirus antibody between clinic visits. Fifty-four cases developed celiac disease autoimmunity at a median age of 4.4 yr. Thirty-six had an intestinal biopsy, of which 27 (75%) were positive for celiac disease. Frequent rotavirus infections predicted a higher risk of celiac disease autoimmunity (compared with zero infections, rate ratio 1.94, 95% confidence interval [CI] 0.39-9.56, for one infection and rate ratio 3.76, 95% CI 0.76-18.7, for > or = 2 infections, rate ratio for trend per increase in number of infections = 1.94, 95% CI 1.04-3.61, p = 0.037). The result was similar after adjustment for gender, ethnic group, maternal education, breast-feeding, day-care attendance, number of siblings, season of birth, and number of HLA DR3-DQ2 haplotypes. This prospective study provides the first indication that a high frequency of rotavirus infections may increase the risk of celiac disease autoimmunity in childhood in genetically predisposed individuals.

Risk of Celiac Disease Autoimmunity and Timing of Gluten Introduction in the Diet of Infants at Increased Risk of Disease

Purpose of the Study. Patients with HLA-DR3 or DR4 alleles are at increased risk for the development of celiac disease. However, not all genetically susceptible individuals develop celiac disease. The objective of this study was to investigate whether there was an association between the timing of exposure to gluten and subsequent development of celiac disease autoimmunity (CDA) in children with a genetic predisposition for celiac disease. Study Population. Children (n = 1560) were identified in the Denver, Colorado, metropolitan area with an increased risk for celiac disease (or type 1 diabetes), defined as having either a first-degree relative with type 1 diabetes or positive cord blood screening for HLA-DR3 or DR4 alleles. This study was conducted over 10 years with a mean follow-up of 4.8 years. Methods. This was a prospective, observational study. Infant diet data were collected during telephone or face-to-face interviews at 3, 6, 9, 12, and 15 months of age. No dietary advice was given to the families. Children had blood drawn at 9, 15, and 24 months and annually thereafter for the measurement of the celiac disease autoantigen, and tissue transglutaminase (tTG). After 1 or 2 positive tTG autoantibody results, small-bowel biopsy was offered to the families, although not all had this procedure performed. The primary outcome of the study was the time to development of CDA defined as the presence of tTG autoantibodies on 2 consecutive results or a positive small-bowel biopsy after a single tTG-positive test. Results. Fifty-one children developed CDA. Children exposed to foods containing wheat, barley, or rye in the first 3 months of life had a 5 times increased odds ratio (P = .02) of CDA as compared with children first exposed to gluten at 4 to 6 months of age. Twenty-five of the CDA-positive children had biopsy-proven celiac disease. In these children, exposure to gluten in the first 3 months of life had a 23 times increased risk (P = .001) of CDA. In the biopsy-proven cohort, children not exposed to gluten until &amp;gt;7 months of age also had a significantly increased risk of CDA (odds ratio: 4; P = .04). There was no association between the development of CDA and the timing of introduction of oats or rice. No protective effect of breastfeeding was found with the development of CDA. Although all children in the cohort were exposed to gluten by 12 months of age, the first positive tTG autoantibody test did not occur until 2 years of age, with a mean age of positive conversion of 4.7 years. Conclusions. In children at increased risk of developing celiac disease, timing of gluten exposure in the diet is associated with the appearance of CDA. Exposure to gluten in the first 3 months of life is thought to be associated with increased risk because of immature or incomplete intestinal barrier function. The authors speculate that late gluten exposure may have been associated with CDA because of greater amounts introduced in the older infants. Reviewer Comments. It is important to understand that this study population was specific children with genetic and family history characteristics at increased risk for the development of celiac disease and may not be generalizable to the entire population. Mean follow-up of this population was just under 5 years, and long-term follow-up of these patients is needed to determine if earlier exposure to gluten simply leads to earlier appearance of CDA and that many (if not all) exposed at-risk children would eventually develop CDA. This study also does not address the relationship between CDA and celiac disease.

Is the timing of infant cereal introduction a risk factor for celiac disease autoimmunity?

Norris JM, Barriga K, Hoffenberg EJ, et al. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA 2005:293:2343-51. ![Figure][1]</img> Figure. Photo by: E. Wooltorton Background: Celiac disease, or gluten-sensitive

Risk of Celiac Disease Autoimmunity and Timing of Gluten Introduction in the Diet of Infants at Increased Risk of Disease

While gluten ingestion is responsible for the signs and symptoms of celiac disease, it is not known what factors are associated with initial appearance of the disease. To examine whether the timing of gluten exposure in the infant diet was associated with the development of celiac disease autoimmunity (CDA). Prospective observational study conducted in Denver, Colo, from 1994-2004 of 1560 children at increased risk for celiac disease or type 1 diabetes, as defined by possession of either HLA-DR3 or DR4 alleles, or having a first-degree relative with type 1 diabetes. The mean follow-up was 4.8 years. Risk of CDA defined as being positive for tissue transglutaminase (tTG) autoantibody on 2 or more consecutive visits or being positive for tTG once and having a positive small bowel biopsy for celiac disease, by timing of introduction of gluten-containing foods into the diet. Fifty-one children developed CDA. Findings adjusted for HLA-DR3 status indicated that children exposed to foods containing wheat, barley, or rye (gluten-containing foods) in the first 3 months of life (3 [6%] CDA positive vs 40 [3%] CDA negative) had a 5-fold increased risk of CDA compared with children exposed to gluten-containing foods at 4 to 6 months (12 [23%] CDA positive vs 574 [38%] CDA negative) (hazard ratio [HR], 5.17; 95% confidence interval [CI], 1.44-18.57). Children not exposed to gluten until the seventh month or later (36 [71%] CDA positive vs 895 [59%] CDA negative) had a marginally increased risk of CDA compared with those exposed at 4 to 6 months (HR, 1.87; 95% CI, 0.97-3.60). After restricting our case group to only the 25 CDA-positive children who had biopsy-diagnosed celiac disease, initial exposure to wheat, barley, or rye in the first 3 months (3 [12%] CDA positive vs 40 [3%] CDA negative) or in the seventh month or later (19 [76%] CDA positive vs 912 [59%] CDA negative) significantly increased risk of CDA compared with exposure at 4 to 6 months (3 [12%] CDA positive vs 583 [38%] CDA negative) (HR, 22.97; 95% CI, 4.55-115.93; P = .001; and HR, 3.98; 95% CI, 1.18-13.46; P = .04, respectively). Timing of introduction of gluten into the infant diet is associated with the appearance of CDA in children at increased risk for the disease.

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Risk of Celiac Disease Autoimmunity and Timing of Gluten Introduction in the Diet of Infants at Increased Risk of Disease