PMID- 26010309 OWN - NLM STAT- MEDLINE DCOM- 20150817 LR - 20240422 IS - 1572-0241 (Electronic) IS - 0002-9270 (Print) IS - 0002-9270 (Linking) VI - 110 IP - 6 DP - 2015 Jun TI - HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study. PG - 915-20 LID - 10.1038/ajg.2015.150 [doi] AB - OBJECTIVES: 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. FAU - Hadley, David AU - Hadley D AD - 1] Division of Population Health Sciences and Education, St. George's, University of London, London, UK [2] TransMed Systems, Pleasanton, California, USA. FAU - Hagopian, William AU - Hagopian W AD - Pacific Northwest Diabetes Research Institute, Seattle, Washington, USA. FAU - Liu, Edwin AU - Liu E AD - 1] Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA [2] Barbara Davis Center, University of Colorado Denver, Aurora, Colorado, USA. FAU - She, Jin-Xiong AU - She JX AD - Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, Georgia, USA. FAU - Simell, Olli AU - Simell O AD - Department of Pediatrics, University of Turku, Turku, Finland. FAU - Akolkar, Beena AU - Akolkar B AD - DDEMD, NIDDK, Bethesda, Maryland, USA. FAU - Ziegler, Anette-G AU - Ziegler AG AD - 1] Institute of Diabetes Research, Helmholtz Zentrum Minchen, Oberschleissheim, Germany [2] Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich, Germany [3] Forschergruppe Diabetes e.V., Neuherberg, Germany. FAU - Rewers, Marian AU - Rewers M AD - Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA. FAU - Krischer, Jeffrey P AU - Krischer JP AD - Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA. FAU - Chen, Wei-Min AU - Chen WM AD - Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. FAU - Onengut-Gumuscu, Suna AU - Onengut-Gumuscu S AD - Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. FAU - Bugawan, Teodorica L AU - Bugawan TL AD - Department of Human Genetics, Roche Molecular Systems, Alameda, California, USA. FAU - Rich, Stephen S AU - Rich SS AD - Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. FAU - Erlich, Henry AU - Erlich H AD - Children's Hospital of Oakland Research Institute, Oakland, California, USA. FAU - Agardh, Daniel AU - Agardh D AD - 1] Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA [2] Department of Clinical Sciences, Lund University, Malmo, Sweden. CN - TEDDY Study Group LA - eng GR - U01 DK063821/DK/NIDDK NIH HHS/United States GR - UC4 DK95300/DK/NIDDK NIH HHS/United States GR - U01 DK63861/DK/NIDDK NIH HHS/United States GR - UC4 DK63863/DK/NIDDK NIH HHS/United States GR - U01 DK63821/DK/NIDDK NIH HHS/United States GR - UC4 DK063821/DK/NIDDK NIH HHS/United States GR - UC4 DK063836/DK/NIDDK NIH HHS/United States GR - HHSN267200700014C/DK/NIDDK NIH HHS/United States GR - UC4 DK63865/DK/NIDDK NIH HHS/United States GR - U01 DK063861/DK/NIDDK NIH HHS/United States GR - UL1 TR001427/TR/NCATS NIH HHS/United States GR - U01 DK063790/DK/NIDDK NIH HHS/United States GR - UC4 DK100238/DK/NIDDK NIH HHS/United States GR - U01 DK63829/DK/NIDDK NIH HHS/United States GR - UL1 TR001082/TR/NCATS NIH HHS/United States GR - UC4 DK63829/DK/NIDDK NIH HHS/United States GR - U01 DK63836/DK/NIDDK NIH HHS/United States GR - P30 DK017047/DK/NIDDK NIH HHS/United States GR - UC4 DK63821/DK/NIDDK NIH HHS/United States GR - UC4 DK063863/DK/NIDDK NIH HHS/United States GR - UL1 TR000064/TR/NCATS NIH HHS/United States GR - UC4 DK63836/DK/NIDDK NIH HHS/United States GR - U01 DK063836/DK/NIDDK NIH HHS/United States GR - U01 DK063829/DK/NIDDK NIH HHS/United States GR - U01 DK063865/DK/NIDDK NIH HHS/United States GR - UC4 DK095300/DK/NIDDK NIH HHS/United States GR - UC4 DK063861/DK/NIDDK NIH HHS/United States GR - U01 DK63865/DK/NIDDK NIH HHS/United States GR - UC4 DK063829/DK/NIDDK NIH HHS/United States GR - U01 DK063863/DK/NIDDK NIH HHS/United States GR - U01 DK63790/DK/NIDDK NIH HHS/United States GR - UC4 DK063865/DK/NIDDK NIH HHS/United States GR - U01 DK63863/DK/NIDDK NIH HHS/United States GR - UC4 DK63861/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PT - Research Support, U.S. Gov't, P.H.S. DEP - 20150526 PL - United States TA - Am J Gastroenterol JT - The American journal of gastroenterology JID - 0421030 RN - 0 (Autoantibodies) RN - 0 (HLA-DP beta-Chains) RN - 0 (HLA-DPB1*04:01 antigen) RN - 0 (HLA-DQ Antigens) RN - 0 (HLA-DQ2 antigen) RN - 0 (HLA-DR3 Antigen) RN - EC 2.3.2.13 (Protein Glutamine gamma Glutamyltransferase 2) RN - EC 2.3.2.13 (Transglutaminases) RN - EC 3.6.1.- (GTP-Binding Proteins) SB - IM MH - Autoantibodies/immunology MH - Autoimmune Diseases/*genetics/immunology MH - Celiac Disease/*genetics/immunology MH - Child MH - Child, Preschool MH - Cohort Studies MH - Female MH - GTP-Binding Proteins/immunology MH - Gene Frequency MH - Genetic Predisposition to Disease MH - HLA-DP beta-Chains/*genetics/immunology MH - HLA-DQ Antigens/genetics/immunology MH - HLA-DR3 Antigen/genetics/immunology MH - Humans MH - Infant MH - Infant, Newborn MH - Logistic Models MH - Male MH - Polymorphism, Single Nucleotide MH - Proportional Hazards Models MH - Protective Factors MH - Protein Glutamine gamma Glutamyltransferase 2 MH - Transglutaminases/immunology PMC - PMC4487515 MID - NIHMS700300 COIS- CONFLICT OF INTEREST Guarantor of the article: David Hadley, PhD. Potential competing interests : None. EDAT- 2015/05/27 06:00 MHDA- 2015/08/19 06:00 PMCR- 2015/12/01 CRDT- 2015/05/27 06:00 PHST- 2015/01/13 00:00 [received] PHST- 2015/04/13 00:00 [accepted] PHST- 2015/05/27 06:00 [entrez] PHST- 2015/05/27 06:00 [pubmed] PHST- 2015/08/19 06:00 [medline] PHST- 2015/12/01 00:00 [pmc-release] AID - ajg2015150 [pii] AID - 10.1038/ajg.2015.150 [doi] PST - ppublish SO - Am J Gastroenterol. 2015 Jun;110(6):915-20. doi: 10.1038/ajg.2015.150. Epub 2015 May 26.