title: HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study.
abstract: OBJECTIVE
  Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1*05:01-DQB1*02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1*03:01-DQB1*03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs.
  
  
  METHODS
  The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B, -DRB3, -DRB4, -DPA1, and -DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex.
  
  
  RESULTS
  After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1*04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1*04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013).
  
  
  CONCLUSIONS
  HLA-DPB1*04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.
authors.affiliation: 1] Division of Population Health Sciences and Education, St. George's, University of London, London, UK [2] TransMed Systems, Pleasanton, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hadley
authors.affiliation: Pacific Northwest Diabetes Research Institute, Seattle, Washington, USA.
authors.forename: William
authors.initials: W
authors.lastname: Hagopian
authors.affiliation: 1] Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA [2] Barbara Davis Center, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Liu
authors.affiliation: Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Jin-Xiong
authors.initials: JX
authors.lastname: She
authors.affiliation: Department of Pediatrics, University of Turku, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.affiliation: DDEMD, NIDDK, Bethesda, Maryland, USA.
authors.forename: Beena
authors.initials: B
authors.lastname: Akolkar
authors.affiliation: 1] Institute of Diabetes Research, Helmholtz Zentrum Mìnchen, Oberschleissheim, Germany [2] Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich, Germany [3] Forschergruppe Diabetes e.V., Neuherberg, Germany.
authors.forename: Anette-G
authors.initials: AG
authors.lastname: Ziegler
authors.affiliation: Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA.
authors.forename: Marian
authors.initials: M
authors.lastname: Rewers
authors.affiliation: Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: Department of Human Genetics, Roche Molecular Systems, Alameda, California, USA.
authors.forename: Teodorica L
authors.initials: TL
authors.lastname: Bugawan
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Children's Hospital of Oakland Research Institute, Oakland, California, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Erlich
authors.affiliation: 1] Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA [2] Department of Clinical Sciences, Lund University, Malmo, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Agardh
mesh_terms: D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D019204:GTP-Binding Proteins / Q000276:immunology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D059868:HLA-DP beta-Chains / Q000235:genetics* / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016015:Logistic Models; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D065840:Protective Factors; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000276:immunology
chemical_list: D001323:Autoantibodies; D059868:HLA-DP beta-Chains; C505113:HLA-DPB1*04:01 antigen; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D015803:HLA-DR3 Antigen; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins