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Multicenter Study
. 2024 Oct 26;14(1):25463.
doi: 10.1038/s41598-024-75496-w.

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

Anna Eurén  1 , Kristian Lynch  2 , Katri Lindfors  1 , Hemang Parikh  2 , Sibylle Koletzko  3   4 , Edwin Liu  5 , Beena Akolkar  6 , William Hagopian  7 , Jeffrey Krischer  2 , Marian Rewers  8 , Jorma Toppari  9   10 , Anette Ziegler  11   12   13 , Daniel Agardh  14 , Kalle Kurppa  15   16   17 ; TEDDY Study Group
Collaborators, Affiliations
Multicenter Study

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

Anna Eurén et al. Sci Rep. .

Abstract

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Absolute incidence of CDA among children with and without CD247 polymorphism as shown by season of birth (panel A), birth cohort (panel B) and age of CDA development (panel C and D).
Fig. 2
Fig. 2
Hazard ratios (± 95% confidence intervals) of spring/summer season of birth on risk of CDA by 10 years of age shown by CD247-G polymorphism and adjusted a for HLA haplogenotypes, country of residence, sex of child and age when child started gluten. a = included in model if not stratified.
Fig. 3
Fig. 3
CD247 mRNA gene expression Log2 TPM levels (± 95% confidence intervals) during first year of life as shown by CD247-G polymorphism of SNP-rs864537 (Panel A) and haplogenotypes CATT/CATT or haplogenotype TGGC of SNPs rs840016, rs864537, rs2056626, rs1723016 (Panel B). Differences in means at each time point tested with adjustment for number of time points (p < 0.01) and for country of residence, sex, family history with type 1 diabetes (matching factors in the source Nested Case Control study) as well as HLA and positive for islet autoantibodies (outcome in source Nested Case Control Study).
Fig. 4
Fig. 4
Absolute incidence of CDA from 0 to 4 years of age by CD247 genotype and seasonal infections reported between age 3 and 6 months of age.
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References

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