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

Abstract

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.

Keywords: Autoimmunity; Food; Gastroenteritis; Rotavirus.

Conflict of interest statement

Conflicts of interest: The authors disclose no conflicts.

Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Risk of CDA between 1 and 4 years of age for (A) GIEs and (B) RIEs reported in the first year of life and within a year before the seroconversion period. *Statistically significant as P < .05 and false discovery rate less than 0.05.

Figure 2

Stratified proportional hazards models of GIE 0 to 3 months before the seroconversion period on the risk of CDA between 1 and 4 years of age stratified by duration of any breastfeeding and HLA-DQ genotype.

Figure 3

Stratified proportional hazards models of GIE 0 to 3 months before the seroconversion period on the risk of CDA between 1 and 4 years of age stratified by season of birth and age at introduction to gluten.

Figure 4

Proportion of TEDDY children reporting a gastrointestinal infection over time among those (A) born in winter or (B) born in summer, and in relation to rotavirus vaccination status in American and Finnish TEDDY children (C) born in winter or (D) born in summer.

Figure 5

Kaplan–Meier curves and log-rank test of CDA by rotavirus vaccine separately for children introduced to gluten (A) before or (B) after 6 months of age.