Risk of pediatric celiac disease according to HLA haplotype and country.

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.).

[1]  S. Virtanen,et al.  Age at first introduction to complementary foods is associated with sociodemographic factors in children with increased genetic risk of developing type 1 diabetes. , 2015, Maternal & child nutrition.

[2]  K. Vehik,et al.  Methods, quality control and specimen management in an international multicentre investigation of type 1 diabetes: TEDDY , 2013, Diabetes/metabolism research and reviews.

[3]  K. Giersiepen,et al.  European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for the Diagnosis of Coeliac Disease , 2012, Journal of pediatric gastroenterology and nutrition.

[4]  Olli Simell,et al.  The Environmental Determinants of Diabetes in the Young (TEDDY): genetic criteria and international diabetes risk screening of 421 000 infants , 2011, Pediatric diabetes.

[5]  K. Vehik,et al.  Enrollment experiences in a pediatric longitudinal observational study: The Environmental Determinants of Diabetes in the Young (TEDDY) study. , 2011, Contemporary clinical trials.

[6]  E. Bonifacio,et al.  A Report on the International Transglutaminase Autoantibody Workshop for Celiac Disease , 2009, The American Journal of Gastroenterology.

[7]  L. Melton,et al.  HLA DQ gene dosage and risk and severity of celiac disease. , 2007, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[8]  Å. Lernmark,et al.  The Environmental Determinants of Diabetes in the Young (TEDDY) study: study design , 2007, Pediatric diabetes.

[9]  M. Rewers,et al.  Rotavirus Infection Frequency and Risk of Celiac Disease Autoimmunity in Early Childhood: A Longitudinal Study , 2006, The American Journal of Gastroenterology.

[10]  M. Rewers,et al.  Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. , 2005, JAMA.

[11]  J. Ilonen,et al.  Natural history of transglutaminase autoantibodies and mucosal changes in children carrying HLA-conferred celiac disease susceptibility , 2005, Scandinavian journal of gastroenterology.

[12]  J. Hugot,et al.  HLA-DQ relative risks for coeliac disease in European populations: a study of the European Genetics Cluster on Coeliac Disease. , 2004, Tissue antigens.

[13]  M. Rewers,et al.  A prospective study of the incidence of childhood celiac disease. , 2003, The Journal of pediatrics.

[14]  J. C. Vitoria,et al.  HLA-DQA1 and HLA-DQB1 Genetic Markers and Clinical Presentation in Celiac Disease , 2002, Journal of pediatric gastroenterology and nutrition.

[15]  M. Rewers,et al.  Transglutaminase antibodies in children with a genetic risk for celiac disease. , 2000, The Journal of pediatrics.

[16]  E. Bonifacio,et al.  Development of celiac disease-associated antibodies in offspring of parents with Type I diabetes , 2000, Diabetologia.

[17]  L. Nyström,et al.  Epidemic of coeliac disease in Swedish children , 2000, Acta paediatrica.

[18]  E. Bonifacio,et al.  Comparison of tissue transglutaminase-specific antibody assays with established antibody measurements for coeliac disease. , 1999, Journal of autoimmunity.

[19]  E. Thorsby,et al.  On the HLA-DQ(alpha 1*0501, beta 1*0201)-associated susceptibility in celiac disease: a possible gene dosage effect of DQB1*0201. , 1993, Tissue antigens.

[20]  M N Marsh,et al.  Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue'). , 1992, Gastroenterology.

[21]  E. Thorsby,et al.  Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer , 1989, The Journal of experimental medicine.