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

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.

The genetics of celiac disease: A comprehensive review of clinical implications

“…HLA-DP alleles were associated with CD risk in 1989 [33,34] and very recently, HLA-DPB1*04:01 has been suggested to reduce the risk to develop anti-TG2 antibodies among DR3-DQ2 children [35]. However, the HLA-DPB1*04:01 allele may be in linkage disequilibrium with risk alleles in HLA-DQ genes and further studies are needed to confirm the independence between those association signals.…”

“…It will be interesting to investigate the implication of this gene in relation to gluten-derived peptides. Special interest lies also on the recent observation of HLA-DPB1*04:01 as reducing the risk of developing anti-TG2 antibodies [35], considered an early marker of CD. This suggests a protective role of HLA-DPB1*04:01 to develop CD, which would be in accordance with the lower frequency of this allele observed in T1D and multiple sclerosis patients compared to controls [108,109].…”

The Environmental Determinants of Diabetes in the Young (TEDDY) Study: 2018 Update

“…Islet autoantibodies usually, but not always, appeared earlier than transglutaminase autoantibodies [77]. TEDDY has reported major country differences in the incidence of celiac disease autoimmunity [78], the clinical features [79], genetic predictors [80, 81], and the role of the early infant diet [82, 83], and infectious factors [59, 60] in risk of celiac disease. Interestingly, gluten introduction before 17 weeks or later than 26 weeks was not associated with increased risk for CDA or CD, controlling for country, HLA genotype, sex, and family history of CD [83].…”

Incidence of Type 1 Diabetes Is Not Increasing in a Population-Based Cohort in Olmsted County, Minnesota, USA

“…Current knowledge suggests that a gluten-free diet may affect dendritic cells and the subsequent development of diabetes (28). HLA markers may help determine the risk of CD in patients with T1D (29, 30). The role of perinatal environment and the microbiome is also under examination.…”