School of Medicine Publications and Presentations
Document Type
Article
Publication Date
4-8-2025
Abstract
Introduction: 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)—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 determine which is the actual risk allele.
Methods: 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 that comprise 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 ten 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.
Results: 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- (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 an RR for DRB1*15:01 against DQB1*06:02 of 7.00 (5.80, 8.44).
Discussion/conclusion: Our results suggest that DRB1*15:01 is the offending HLAII allele and that DR15 allotypes underlie the increased FEI risk in HAPs.
Recommended Citation
Diego, V. P., Luu, B. W., Almeida, M. A., Rajalingam, R., Hofmann, M., Galan, J. A., ... & Howard, T. E. (2025). 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. Frontiers in Genetics, 16, 1506862. https://doi.org/10.3389/fgene.2025.1506862
Publication Title
Frontiers in Genetics
DOI
10.3389/fgene.2025.1506862
Academic Level
faculty
Mentor/PI Department
Office of Human Genetics
Comments
© 2025 Diego, Luu, Almeida, Rajalingam, 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) and the copyright owner(s) 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.