HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study

Affiliations

¹ 1] Division of Population Health Sciences and Education, St. George's, University of London, London, UK [2] TransMed Systems, Pleasanton, California, USA.
² Pacific Northwest Diabetes Research Institute, Seattle, Washington, USA.
³ 1] Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA [2] Barbara Davis Center, University of Colorado Denver, Aurora, Colorado, USA.
⁴ Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, Georgia, USA.
⁵ Department of Pediatrics, University of Turku, Turku, Finland.
⁶ DDEMD, NIDDK, Bethesda, Maryland, USA.
⁷ 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.
⁸ Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA.
⁹ Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA.
¹⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
¹¹ Department of Human Genetics, Roche Molecular Systems, Alameda, California, USA.
¹² Children's Hospital of Oakland Research Institute, Oakland, California, USA.
¹³ 1] Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA [2] Department of Clinical Sciences, Lund University, Malmo, Sweden.

PMID: 26010309
PMCID: PMC4487515
DOI: 10.1038/ajg.2015.150

HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study

David Hadley et al. Am J Gastroenterol. 2015 Jun.

. 2015 Jun;110(6):915-20.

doi: 10.1038/ajg.2015.150. Epub 2015 May 26.

Authors

Affiliations

¹ 1] Division of Population Health Sciences and Education, St. George's, University of London, London, UK [2] TransMed Systems, Pleasanton, California, USA.
² Pacific Northwest Diabetes Research Institute, Seattle, Washington, USA.
³ 1] Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA [2] Barbara Davis Center, University of Colorado Denver, Aurora, Colorado, USA.
⁴ Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, Georgia, USA.
⁵ Department of Pediatrics, University of Turku, Turku, Finland.
⁶ DDEMD, NIDDK, Bethesda, Maryland, USA.
⁷ 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.
⁸ Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA.
⁹ Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA.
¹⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
¹¹ Department of Human Genetics, Roche Molecular Systems, Alameda, California, USA.
¹² Children's Hospital of Oakland Research Institute, Oakland, California, USA.
¹³ 1] Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA [2] Department of Clinical Sciences, Lund University, Malmo, Sweden.

PMID: 26010309
PMCID: PMC4487515
DOI: 10.1038/ajg.2015.150

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.

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Conflict of interest statement

CONFLICT OF INTEREST

Guarantor of the article: David Hadley, PhD.

Potential competing interests : None.

References

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HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study

Affiliations

HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Research Materials