{"doi":"10.1101/2024.12.20.24319436","title":"Linkage between HLA-B8 and HLA-DQ2.5 Contributes to Ancestry-Dependent Genetic Risk for Celiac Disease","abstract":"Abstract Background Most genetic studies on celiac disease (CeD) have focused on individuals of European descent. Limited data are available for the Hispanic and black populations. Methods We analyzed whole-genome sequencing data, electronic health records (EHR), and laboratory results from the All of Us Research Program. We identified 3,481 individuals with CeD through EHR, self-reporting, or both. 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. Five sex-, age-, and ancestry-matched controls per case were selected for the assessment of genetic and clinical risk factors. Results 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%). Among individuals carrying the DQ2.5 ( DQA1*05:01-DQB1*02:01 haplotype), HLA-B8 was present in 72.3% of Europeans, 42.3% of Admixed Americans, and lower in Africans. This linkage disequilibrium was higher in CeD patients than in controls across all three ancestries. A polygenic risk score distinguished seropositive CeD from controls with 86% accuracy. Incorporating clinical risk factors, including family history, hypothyroidism, diarrhea, vitamin D deficiency, and anemia, increased predictive accuracy to 92%. The model identified 93% of CeD patients with tTG-IgA levels greater than 10 IU/mL. Conclusion Linkage between HLA-B8 and DQ2.5 differs significantly among individuals of European, admixed American, and African ancestry, contributing to ancestry-dependent genetic risk for CeD. Summary Using data from the All of Us Research Program , we found that HLA-DQ2.5, a key genetic risk factor for celiac disease, is present in European (11.6%), Admixed American (8.1%), and African (8.1%) populations, but its disease penetrance differs significantly by ancestry.","journal":"medRxiv","year":2024,"id":507994,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":0.0,"corpus_rank":10062,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.5849,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1116450,"name":"Xin Long","orcid":"0000-0002-9817-5858","position":2,"is_corresponding":false},{"id":1230185,"name":"Mary‐Joe Touma","orcid":"0000-0002-1657-1276","position":3,"is_corresponding":false},{"id":1360086,"name":"Ioana Smith","orcid":null,"position":4,"is_corresponding":false},{"id":281004,"name":"Suzanne K. Lewis","orcid":"0000-0002-6651-4499","position":5,"is_corresponding":false},{"id":240348,"name":"Chao Xing","orcid":"0000-0002-1838-0502","position":6,"is_corresponding":false},{"id":319713,"name":"Ezra Burstein","orcid":"0000-0003-4341-6367","position":7,"is_corresponding":false},{"id":420696,"name":"Peter H.R. Green","orcid":"0000-0001-6839-9634","position":8,"is_corresponding":false},{"id":1360087,"name":"M. Alkalay","orcid":null,"position":9,"is_corresponding":false},{"id":104166,"name":"Alexandre Bolze","orcid":"0000-0001-7399-2766","position":10,"is_corresponding":false},{"id":871564,"name":"Xiao‐Fei Kong","orcid":"0000-0001-9983-2373","position":11,"is_corresponding":false},{"id":1360085,"name":"Hemanth Karnati","orcid":null,"position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T02:11:06.395600Z","pmid":"42078408","pmcid":"PMC13131749","fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}