HLA-DPB1∗04:01 protects genetically susceptible children from celiac disease autoimmunity in the TEDDY study

David Hadley, William Hagopian, Edwin Liu, Jin-Xiong She, Olli Simell, Beena Akolkar, Anette G. Ziegler, Marian Rewers, Jeffrey P. Krischer, Wei Min Chen, Suna Onengut-Gumuscu, Teodorica L. Bugawan, Stephen S. Rich, Henry Erlich, Daniel Agardh

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14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)915-920
Number of pages6
JournalAmerican Journal of Gastroenterology
Volume110
Issue number6
DOIs
StatePublished - Jun 10 2015

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Hadley, D., Hagopian, W., Liu, E., She, J-X., Simell, O., Akolkar, B., Ziegler, A. G., Rewers, M., Krischer, J. P., Chen, W. M., Onengut-Gumuscu, S., Bugawan, T. L., Rich, S. S., Erlich, H., & Agardh, D. (2015). HLA-DPB1∗04:01 protects genetically susceptible children from celiac disease autoimmunity in the TEDDY study. American Journal of Gastroenterology, 110(6), 915-920. https://doi.org/10.1038/ajg.2015.150