Linkage between HLA-B8 and HLA-DQ2.5 contributes to ancestry-dependent risk for celiac disease

Limited genetic studies on celiac disease (CeD) are available for the Hispanic and black populations. We identified 3,481 individuals with CeD from the All of Us Research Program. Of these, 2,899 carried one of the four well-established risk haplotypes, including 262 of admixed American (89% Hispanic) and 108 of African (70% black) ancestry. An enrichment in the DQB1*02:01 allele was observed in CeD patients across all ancestries, with the strongest association in Europeans (32.3% vs. 11.6%), followed by Americans (18.5% vs. 8.1%) and Africans (15.7% vs. 8.1%). HLA-B8 conferred an additive risk for CeD independent of HLA-DQ2.5 across all three ancestries. The B8-DQ2.5 haplotype was significantly enriched in individuals with CeD but occurred at substantially lower frequencies in individuals with admixed American (3.2%) and African ancestry (1.2%) than in those with European ancestry (7.3%), accounting for ∼34% and 38% of the lower CeD prevalence, respectively. The frequency of the B8-DQ2.5 haplotype contributes to ancestry-dependent differences in CeD prevalence.