Original article
Alimentary tract
Factors That Increase Risk of Celiac Disease Autoimmunity After a Gastrointestinal Infection in Early Life

https://doi.org/10.1016/j.cgh.2016.10.033Get rights and content

Background & Aims

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.

Methods

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.

Results

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).

Conclusions

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.

Section snippets

Study Cohort

The TEDDY study, approved by local Ethical Institutional Review Boards and monitored by an External Advisory Board formed by the National Institutes of Health, follows up a birth cohort of 8676 children with 1 of 10 HLA-DR-DQ genotypes associated with type 1 diabetes and/or celiac disease,8 located in Finland; Germany; and Sweden; and Colorado, Georgia/Florida, and Washington state in the United States.9 Of the infants enrolled, 8280 (95.4%) carried one of the following HLA genotypes:

Temporal Association Between Infectious Episodes and Risk of Celiac Disease Autoimmunity

Complete demographic and dietary information was available for 97.2% (6148 of 6327) of subjects (Table 1). A total of 13,881 GIEs and 79,816 RIEs were recorded during the study period. RIEs and GIEs peaked between 6 and 9 months of age (69.7% of children reporting) and 15 to 18 months of age (18.2% of children reporting), respectively (Supplementary Figure 3A). The incidence of RIEs and GIEs was highest in February (5.0 and 1.09 per person-years, respectively) and lowest in July (1.6 and 0.32

Discussion

In TEDDY, gastrointestinal infections occurring 3 months before the seroconversion period may trigger CDA in children carrying HLA risk genotypes for celiac disease. The increased risk after a gastrointestinal infection is modified further by several early life factors including the duration of any breastfeeding, age of gluten introduction, season of birth, HLA genotype, and status of rotavirus vaccination, pointing to important interactions between diet and infections in the development of CDA

Conclusions

A gastrointestinal infection increases CDA risk in the following 3-month period in children at genetic risk for celiac disease. The timing of infection is important and its effect on CDA risk is modified further by early introduction to gluten in children born in winter, short duration of any breastfeeding in non-DQ2 risk carriers, and status of rotavirus vaccination. This indicates that various exposures during early childhood may trigger CDA and encourages further work on the role of viruses,

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    Conflicts of interest The authors disclose no conflicts.

    Funding This study was funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, and UC4 DK106955 grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and contract HHSN267200700014C from the National Institutes of Health (NIH), as well as the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and the Centers for Disease Control and Prevention (CDC). This work was supported in part by the National Center for Advancing Translational Sciences (NCATS) Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR001082).

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