title: Risk of pediatric celiac disease according to HLA haplotype and country.
abstract: 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.).
authors.affiliation: From 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.).
authors.forename: Edwin
authors.initials: E
authors.lastname: Liu
authors.forename: Hye-Seung
authors.initials: HS
authors.lastname: Lee
authors.forename: Carin A
authors.initials: CA
authors.lastname: Aronsson
authors.forename: William A
authors.initials: WA
authors.lastname: Hagopian
authors.forename: Sibylle
authors.initials: S
authors.lastname: Koletzko
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Rewers
authors.forename: George S
authors.initials: GS
authors.lastname: Eisenbarth
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.forename: Ville
authors.initials: V
authors.lastname: Simell
authors.forename: Daniel
authors.initials: D
authors.lastname: Agardh
mesh_terms: D000906:Antibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000453:epidemiology / Q000235:genetics*; D002446:Celiac Disease / Q000453:epidemiology / Q000235:genetics*; D002675:Child, Preschool; D005060:Europe / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics*; D015803:HLA-DR3 Antigen / Q000235:genetics*; D015804:HLA-DR4 Antigen / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D011446:Prospective Studies; D012306:Risk; D011503:Transglutaminases / Q000276:immunology; D014481:United States / Q000453:epidemiology
chemical_list: D000906:Antibodies; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D015803:HLA-DR3 Antigen; D015804:HLA-DR4 Antigen; D011503:Transglutaminases