A case-cohort longitudinal study for the analysis of microbial associations and viruses on the risk of celiac disease (MAVRiC)

Celiac disease etiopathogenesis requires genetic predisposition and exposure to gluten before a child can develop the chronic autoimmune disorder. However, these factors alone are not sufficient. Even a child with persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity (CDA), does not necessarily develop celiac disease. Larger longitudinal studies are needed to determine the impact of time-varying infections and gut microorganisms on the subsequent and specific risk of celiac disease. The aim was to design a celiac disease case-cohort longitudinal study using The Environmental Determinants of Diabetes in the Young (TEDDY) study. Following the TEDDY cohort up age 3-years, CDA was confirmed in 704 of the 6132 genetically at-risk children. Celiac disease onset was defined as the age CDA developed when followed by a biopsy-proven diagnosis. A competing risk analysis was performed on celiac disease onset cases (CD-onset) as well as CDA children with no diagnosis (CDA-only) and results show genetic factors (additional HLA-DR3-DQ2 haplotype, higher non-HLA polygenic risk score, sex-girl) and a more rapid increase in gluten-consumption correlate with significant increased risk of both outcomes. However, reports of virus-related respiratory infections in August to October during follow-up correlated with an increased risk of a CD-onset but not with CDA-only. To create a case-cohort study, a sub-cohort of 561 children (9% sampling fraction) was first randomly selected to represent the TEDDY cohort over time while at risk of CDA. It included 483 children followed until age 3-years and 78 children followed before developing CDA (CDA-only n=41/78, CD-onset n=37/78). All incident CD-onset children (N=306) were included to form the case group. This case-cohort will be utilized to analyze virus antibodies and bacteriome from longitudinal plasma and stool samples (the Microbial Associations and Viruses on the Risk of Celiac disease study, MAVRiC).