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Risk of pediatric celiac disease according to HLA haplotype and country
Edwin Liu1, Hye-Seung Lee, Carin A Aronsson
1From the Digestive Health Institute, Children's Hospital Colorado (E.L.), and the Barbara Davis Center (E.L., M.J.R., G.S.E.), University of Colorado Denver, Aurora; the Pediatrics Epidemiology Center, University of South Florida, Tampa (H.-S.L.); the Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmo, Sweden (C.A.A., D.A.); Pacific Northwest Diabetes Research Institute, Seattle (W.A.H.); Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich (S.K.), the Center for Regenerative Therapies Dresden, Technische Universitaet Dresden, Dresden (E.B.), and Forschergruppe Diabetes, Helmholz Zentrum München, Neuherberg (E.B.) - all in Germany; the School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (P.J.B.); and the Department of Pediatrics, University of Turku, Turku University Hospital, Turku, Finland (V.S.).
Insights
Children with the HLA haplotype DR3-DQ2 face a significantly higher risk of developing celiac disease autoimmunity and celiac disease, particularly those who are homozygotes. Environmental factors, such as country of residence, may also influence celiac disease risk.
Area of Science:
- Pediatric immunology
- Gastroenterology
- Genetics
Background:
- HLA haplotype DR3-DQ2 and DR4-DQ8 are linked to increased celiac disease risk.
- Serum antibodies against tissue transglutaminase (tTG) are present in nearly all children with celiac disease.
Purpose of the Study:
- To prospectively investigate the development of celiac disease autoimmunity and celiac disease in children with specific HLA haplotypes.
- To quantify the risk associated with HLA DR3-DQ2 homozygosity and heterozygosity.
Main Methods:
- A prospective study of 6403 children with HLA haplotype DR3-DQ2 or DR4-DQ8 from birth across four countries.
- Celiac disease autoimmunity defined by two positive tTG antibody tests (≥3 months apart).
- Celiac disease defined by biopsy or persistently high tTG antibodies.
Main Results:
- Celiac disease autoimmunity developed in 12% of children over a median follow-up of 60 months.
- Children with DR3-DQ2 homozygosity had a 5.70-fold increased hazard ratio for celiac disease autoimmunity compared to lowest-risk genotypes.
- Residence in Sweden was independently associated with a 1.90-fold increased risk of celiac disease autoimmunity.
Conclusions:
- Children with HLA haplotype DR3-DQ2, especially homozygotes, are at high risk for early-onset celiac disease autoimmunity and celiac disease.
- The elevated risk in Sweden underscores the need to investigate environmental factors in celiac disease development.
- Findings support early monitoring for children with high-risk HLA genotypes.
Background:
The presence of HLA haplotype DR3-DQ2 or DR4-DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG).
Methods:
We studied 6403 children with HLA haplotype DR3-DQ2 or DR4-DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies.
Results:
The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3-DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3-DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4-DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25).
Conclusions:
Children with the HLA haplotype DR3-DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries highlights the importance of studying environmental factors associated with celiac disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).
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