title: Identification of Non-HLA Genes Associated with Celiac Disease and Country-Specific Differences in a Large, International Pediatric Cohort.
abstract: OBJECTIVE
  There are significant geographical differences in the prevalence and incidence of celiac disease that cannot be explained by HLA alone. More than 40 loci outside of the HLA region have been associated with celiac disease. We investigated the roles of these non-HLA genes in the development of tissue transglutaminase autoantibodies (tTGA) and celiac disease in a large international prospective cohort study.
  
  
  METHODS
  A total of 424,788 newborns from the US and European general populations and first-degree relatives with type 1 diabetes were screened for specific HLA genotypes. Of these, 21,589 carried 1 of the 9 HLA genotypes associated with increased risk for type 1 diabetes and celiac disease; we followed 8676 of the children in a 15 y prospective follow-up study. Genotype analyses were performed on 6010 children using the Illumina ImmunoChip. Levels of tTGA were measured in serum samples using radio-ligand binding assays; diagnoses of celiac disease were made based on persistent detection of tTGA and biopsy analysis. Data were analyzed using Cox proportional hazards analyses.
  
  
  RESULTS
  We found 54 single-nucleotide polymorphisms (SNPs) in 5 genes associated with celiac disease (TAGAP, IL18R1, RGS21, PLEK, and CCR9) in time to celiac disease analyses (10-4>P>5.8x10-6). The hazard ratios (HR) for the SNPs with the smallest P values in each region were 1.59, 1.45, 2.23, 2.64, and 1.40, respectively. Outside of regions previously associated with celiac disease, we identified 10 SNPs in 8 regions that could also be associated with the disease (P<10-4). A SNP near PKIA (rs117128341, P = 6.5x10-8, HR = 2.8) and a SNP near PFKFB3 (rs117139146, P<2.8x10-7, HR = 4.9) reached the genome-wide association threshold in subjects from Sweden. Analyses of time to detection of tTGA identified 29 SNPs in 2 regions previously associated with celiac disease (CTLA4, P = 1.3x10-6, HR = 0.76 and LPP, P = 2.8x10-5, HR = .80) and 6 SNPs in 5 regions not previously associated with celiac disease (P<10-4); non-HLA genes are therefore involved in development of tTGA.
  
  
  CONCLUSIONS
  In conclusion, using a genetic analysis of a large international cohort of children, we associated celiac disease development with 5 non-HLA regions previously associated with the disease and 8 regions not previously associated with celiac disease. We identified 5 regions associated with development of tTGA. Two loci associated with celiac disease progression reached a genome-wide association threshold in subjects from Sweden.
authors.affiliation: Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA, United States of America.
authors.forename: Ashok
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Pediatric Epidemiology Center, Department of Pediatrics, University of South Florida, Tampa, FL, United States of America.
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Pediatric Epidemiology Center, Department of Pediatrics, University of South Florida, Tampa, FL, United States of America.|Division of Population Health Sciences and Education, St George's University of London, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Hadley
authors.affiliation: Pacific Northwest Diabetes Research Institute, Seattle, WA, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Hagopian
authors.affiliation: Digestive Health Institute, Children's Hospital Colorado, University of Colorado Denver, Aurora, CO, United States of America.
authors.forename: Edwin
authors.initials: E
authors.lastname: Liu
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States of America.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States of America.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: Department of Pediatrics, University of Turku, Turku, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Simell
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, United States of America.
authors.forename: Marian
authors.initials: M
authors.lastname: Rewers
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, and Klinikum rechts der Isar, Technische Universität München, and Forschergruppe Diabetes e.V., Munich-Neuherberg, Germany.
authors.forename: Anette-G
authors.initials: AG
authors.lastname: Ziegler
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Malmö, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Lernmark
authors.affiliation: Department of Pediatrics, University of Turku, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.affiliation: Department of Pediatrics, University of Turku, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Pediatric Epidemiology Center, Department of Pediatrics, University of South Florida, Tampa, FL, United States of America.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
authors.affiliation: National Institutes of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Beena
authors.initials: B
authors.lastname: Akolkar
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States of America.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Diabetes and Celiac Disease Unit, Lund University, Malmo, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Agardh
authors.affiliation: Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA, United States of America.
authors.forename: Jin-Xiong
authors.initials: JX
authors.lastname: She
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000097:blood*; D001706:Biopsy; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D018450:Disease Progression; D005060:Europe; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000276:immunology; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007391:International Cooperation; D008297:Male; D010372:Pediatrics; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013548:Sweden; D011503:Transglutaminases / Q000235:genetics* / Q000276:immunology; D014481:United States
chemical_list: D001323:Autoantibodies; D006680:HLA Antigens; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins