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HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study.
Am J Gastroenterol 2015; 110(6):915-20AJ

Abstract

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.

Authors+Show Affiliations

1] Division of Population Health Sciences and Education, St. George's, University of London, London, UK [2] TransMed Systems, Pleasanton, California, USA.Pacific Northwest Diabetes Research Institute, Seattle, Washington, USA.1] Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA [2] Barbara Davis Center, University of Colorado Denver, Aurora, Colorado, USA.Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, Georgia, USA.Department of Pediatrics, University of Turku, Turku, Finland.DDEMD, NIDDK, Bethesda, Maryland, USA.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.Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA.Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA.Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.Department of Human Genetics, Roche Molecular Systems, Alameda, California, USA.Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.Children's Hospital of Oakland Research Institute, Oakland, California, USA.1] Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA [2] Department of Clinical Sciences, Lund University, Malmo, Sweden.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

26010309

Citation

Hadley, David, et al. "HLA-DPB1*04:01 Protects Genetically Susceptible Children From Celiac Disease Autoimmunity in the TEDDY Study." The American Journal of Gastroenterology, vol. 110, no. 6, 2015, pp. 915-20.
Hadley D, Hagopian W, Liu E, et al. HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study. Am J Gastroenterol. 2015;110(6):915-20.
Hadley, D., Hagopian, W., Liu, E., She, J. X., Simell, O., Akolkar, B., ... Agardh, D. (2015). HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study. The American Journal of Gastroenterology, 110(6), pp. 915-20. doi:10.1038/ajg.2015.150.
Hadley D, et al. HLA-DPB1*04:01 Protects Genetically Susceptible Children From Celiac Disease Autoimmunity in the TEDDY Study. Am J Gastroenterol. 2015;110(6):915-20. PubMed PMID: 26010309.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study. AU - Hadley,David, AU - Hagopian,William, AU - Liu,Edwin, AU - She,Jin-Xiong, AU - Simell,Olli, AU - Akolkar,Beena, AU - Ziegler,Anette-G, AU - Rewers,Marian, AU - Krischer,Jeffrey P, AU - Chen,Wei-Min, AU - Onengut-Gumuscu,Suna, AU - Bugawan,Teodorica L, AU - Rich,Stephen S, AU - Erlich,Henry, AU - Agardh,Daniel, AU - ,, Y1 - 2015/05/26/ PY - 2015/01/13/received PY - 2015/04/13/accepted PY - 2015/5/27/entrez PY - 2015/5/27/pubmed PY - 2015/8/19/medline SP - 915 EP - 20 JF - The American journal of gastroenterology JO - Am. J. Gastroenterol. VL - 110 IS - 6 N2 - 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. SN - 1572-0241 UR - https://www.unboundmedicine.com/medline/citation/26010309/HLA_DPB1_04:01_Protects_Genetically_Susceptible_Children_from_Celiac_Disease_Autoimmunity_in_the_TEDDY_Study_ L2 - http://Insights.ovid.com/pubmed?pmid=26010309 DB - PRIME DP - Unbound Medicine ER -