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BRIEF RESEARCH REPORT article

Front. Genet.
Sec. Immunogenetics
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1506862
This article is part of the Research Topic Exploring Immunogenetics in Immune-Mediated Inflammatory Diseases: Unveiling Genetic Insights for Precision Medicine View all articles

Disentangling Effects of the DR and DQ Isomers Encoded by the HLA class II Haplotype DRB1*15:01/DQB1*06:02 to Help Establish the True Risk Allele for FVIII Inhibitor Development in Hemophilia A

Provisionally accepted
Vincent P Diego Vincent P Diego 1*Bernadette W. Luu Bernadette W. Luu 2Marcio Almeida Marcio Almeida 1Rajalingam Raja Rajalingam Raja 3Marco Hofmann Marco Hofmann 4Jacob A Galan Jacob A Galan 1Eron Grant Manusov Eron Grant Manusov 1Jerry S Powell Jerry S Powell 2,5Long V Dinh Long V Dinh 2Henry Mead Henry Mead 6Huy Huynh Huy Huynh 7Anne M Verhagen Anne M Verhagen 7Juan Peralta Juan Peralta 1Paul V Lehmann Paul V Lehmann 8,9Satish Kumar Satish Kumar 1Eli J Fine Eli J Fine 10Joanne E Curran Joanne E Curran 1Harald Goring Harald Goring 1Miguel A Escobar Miguel A Escobar 11,12Sarah Williams-Blangero Sarah Williams-Blangero 1Eugene Maraskovsky Eugene Maraskovsky 7John Blangero John Blangero 1Tom E. Howard Tom E. Howard 1,13,2
  • 1 Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX, United States
  • 2 Haplogenics Corporation, Brownsville, TX, United States
  • 3 Immunogenetics and Transplantation Laboratory, Department of Surgery, School of Medicine, University of California at San Francisco, San Francisco, CA, United States
  • 4 CSL Innovation GmbH, Marburg, Germany
  • 5 Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California Davis, Davis, CA, United States
  • 6 Global Medical Affairs, BioMarin, Novato, CA, United States
  • 7 CSL Limited Research, Bio21 Institute, Melbourne, Australia
  • 8 Cellular Technology Limited (CTL), Shaker Heights, OH, United States
  • 9 Departments of Pathology and Neurology, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
  • 10 Consultant, Atlanta, GA, United States
  • 11 Gulf States Hemophilia and Thrombophilia Center, Houston, TX, United States
  • 12 Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center, Houston, TX, United States
  • 13 VA Texas Valley Coastal Bend Health Care System, Veterans Health Administration, United States Department of Veterans Affairs, Harlingen, Texas, United States

The final, formatted version of the article will be published soon.

    Hemophilia-A (HA) patients (HAPs) with the human-leukocyte-antigen (HLA)-class-II (HLAII) haplotype DRB1*15:01/DQB1*06:02, and thus antigen-presenting-cells which express HLAII β-polypeptide-chains that form heterodimers of DR15- and DQ6-serotypes, respectively, have an increased risk of developing "factor (F)VIII inhibitors (FEIs)", i.e., neutralizing-antibodies against the therapeutic-FVIII-proteins (tFVIIIs) infused to prevent/arrest bleeding. As DRB1*15:01 and DQB1*06:02 exist in strong linkage-disequilibrium, association-analysis cannot disentangle which is the actual risk allele. To establish the true risk-allele of this haplotype, we analyzed the tFVIII-derived-peptides (tFVIII-dPs) bound to either the DR- or DQ-molecules comprising the individual-HLAII-repertoires expressed by monocyte-derived dendritic-cells obtained from 25 normal-blood-donors and six HAPs, four without and two with FEIs. We performed log-linear-mixed model analyses, where the dependent-variable is the log of the measured peptide count. Under Model 1, we analyzed an HLAII allele predictor consisting of 10 levels (four DRB1 and six DQB1 alleles) in the fixed effects, and variables in the random effects to account for non-independence. Model 2---where the HLAII-allele variable consisted of only DRB1*15:01 and DQB1*06:02---compares the HLAII alleles. Relative to the Model 1 reference, DRB1*15:01 and DQB1*06:02 significantly increased tFVIII-derived-peptide counts, and DRB1*15:01 contributed significantly more than DQB1*06:02. Reported as risk-ratios (RRs) and their 95%-confidence interval (CI) lower-bound (LB) and upper-bound (UB), we found a RR (95%-CI-LB, -UB) of 14.16 (10.38, 19.33) and 1.76 (1.24, 2.50) for DRB1*15:01 and DQB1*06:02, respectively. Under Model 2, we found a RR for DRB1*15:01 against DQB1*06:02 of 7.00 (5.80, 8.44). Our results suggest that DRB1*15:01 is the offending-HLAII-allele and DR15-allotypes underlie the increased FEI-risk in HAPs.

    Keywords: CI, confidence interval, DCs, dendritic cells, eCDFs, empirical cumulative distribution functions, F, factor, FVIII, factor VIII, FVIII:C, FVIII coagulant activity, FED Study, FVIII Epitope Determination Study, FEIs, FVIII inhibitors

    Received: 06 Oct 2024; Accepted: 06 Jan 2025.

    Copyright: © 2025 Diego, Luu, Almeida, Raja, Hofmann, Galan, Manusov, Powell, Dinh, Mead, Huynh, Verhagen, Peralta, Lehmann, Kumar, Fine, Curran, Goring, Escobar, Williams-Blangero, Maraskovsky, Blangero and Howard. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Vincent P Diego, Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX, United States

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