Gene Variant, Season of Birth Identified as Celiac Disease Risk Factors

Season of birth, genetic factors, and early-life infections were found to influence the risk of celiac disease autoimmunity, with a significant effect observed in children with a specific gene variant, suggesting the need for further research into gene-environment interactions in celiac disease development, according to a study.¹

When someone with celiac disease eats gluten, their immune system reacts, damaging the lining of the small intestine and preventing proper nutrient absorption, a condition known as malabsorption. | Image credit: weyo - stock.adobe.com

The observational study, published in Scientific Reports, aimed to explore why only a minority of genetically predisposed individuals develop celiac disease despite widespread genetic risk and to uncover potential biological processes, such as seasonal immune system changes and prenatal influences, that contribute to the etiology of celiac disease and other autoimmune diseases. This was the first study to explicitly explain why season of birth affects celiac disease risk.

Celiac disease is an autoimmune condition triggered by consuming gluten, a protein found in wheat, barley, and rye.² When someone with celiac disease eats gluten, their immune system reacts, damaging the lining of the small intestine and preventing proper nutrient absorption, a condition known as malabsorption. This intestinal damage can lead to symptoms like diarrhea, fatigue, weight loss, bloating, and anemia, and can cause serious complications if left untreated. In children, malabsorption may also affect growth and development. Although there is no cure for celiac disease, most individuals can manage symptoms and promote healing by following a strict gluten-free diet.

Data were pulled from the long-term observational TEDDY study (NCT00279318), which was designed to investigate environmental triggers for type 1 diabetes (T1D) and celiac disease in children genetically predisposed to these conditions. It follows participants from birth up to 15 years of age across 3 centers in the US and Europe.

Between 2004 and 2010, 424,788 infants were screened for human leukocyte antigen (HLA) genotypes associated with type 1 diabetes and celiac disease risk. Overall, 21,583 infants were identified as carrying the relevant genotypes, and 8676 families joined the study. Ultimately, 6523 children were followed for celiac disease autoimmunity (CDA) up to age 10, with 1262 developing CDA.

Study visits were conducted quarterly until the age of 4 years and biannually thereafter. Data on maternal and child illnesses were collected via postpartum questionnaires and caregiver diaries, with infections categorized by type and coded using ICD-10. Blood samples were taken at every visit, with transglutaminase antibodies (tTGA) measured annually from 24 months onward to identify CDA. RNA sequencing of whole-blood samples from selected participants was conducted to investigate gene expression differences related to season of birth and genetic factors.

The incidence of CDA varied seasonally, with higher rates observed for children born between April and July. By the age of 10, children born in spring or summer showed an increased risk of CDA (HR, 1.29; 95% CI, 1.09-1.53; P = .004) compared with other seasons, with a slightly lower but still significant risk increase by the age of 5 (HR, 1.18; 95% CI, 1.03-1.34; P = .01). These findings remained consistent after adjusting for HLA haplogenotypes, sex, and country.

Among non-HLA genetic factors, 16 single nucleotide polymorphisms (SNPs) were associated with CDA risk. The CD247 SNP rs864537 demonstrated a significant interaction with season of birth on both additive and multiplicative scales. Children with the CD247-AA genotype born in spring/summer exhibited an elevated risk (95% CI, −0.76 to −0.16), while those without this genotype did not show a significant association. The findings suggest a potential interplay between genetic predisposition and environmental factors like seasonality in CDA development.

The increased CDA risk was absent in children carrying the minor G allele of rs864537, highlighting a potential interaction between genetic susceptibility and environmental factors like seasonality in CDA development.

The authors determined that variations in the CD247 gene, like rs864537, may affect autoimmunity, with defective expression in systemic lupus erythematosus linked to T-cell dysfunction and impaired immune tolerance.

Season of birth may influence immune function through epigenetic programming during pregnancy, such as DNA methylation and histone modification. The association between season of birth and CDA was significant when gluten was introduced before 7 months, with early gluten exposure and infections potentially synergizing to increase risk, especially with early cessation of breastfeeding.

Study limitations included reliance on self-reported data, a predominantly White cohort, and a study design primarily focused on T1D, which may underrepresent HLA-DQ alleles relevant to celiac disease.

The authors conclude, “Information obtained from the present study can contribute to providing a foundation for risk modeling and biomarker discovery that could be exploited in designing future studies aiming to improve our understanding of CD and other autoimmune diseases.”

References

1. Eurén A, Lynch K, Lindfors K, et al. Risk of celiac disease autoimmunity is modified by interactions between CD247 and environmental exposures. Sci Rep. Published online October 26, 2024. doi:10.1038/s41598-024-75496-w

2. Celiac disease. Mayo Clinic. Accessed January 15, 2025. https://www.mayoclinic.org/diseases-conditions/celiac-disease/symptoms-causes/syc-20352220