A scan of pleiotropic immune mediated disease genes identifies novel determinants of baseline FVIII inhibitor status in hemophilia A

Authors

• Marcio A. Almeida, University of Texas Rio Grande Valley School of Medicine
• Vincent P. Diego, University of Texas Rio Grande Valley School of Medicine
• Kevin R. Viel, Histonis, Inc.
• Bernadette W. Luu, Haplogenics Corporation
• Karin Haack, Texas Biomedical Research Institute
• Raja Rajalingam, UCSF School of Medicine
• Afshin Ameri, Medical College of Georgia
• Meera Chitlur, Wayne State University
• Natalia Rydz, Cumming School of Medicine
• David Lillicrap, Queen’s University
• Raymond G. Watts, LSU Health Sciences Center - New OrleansFollow
• Craig M. Kessler, Georgetown University
• Christopher Ramsey, Clever Culture Systems
• Long V. Dinh, Haplogenics Corporation
• Benjamin Kim, Consultant
• Jerry S. Powell, Haplogenics Corporation
• Eron G. Manusov, University of Texas Rio Grande Valley School of Medicine
• Juan M. Peralta, University of Texas Rio Grande Valley School of Medicine
• Ruayda Bouls, University of Texas Rio Grande Valley School of Medicine
• Shirley M. Abraham, UNM School of Medicine
• Yu Min Shen, UT Southwestern Medical School
• Carlos M. Murillo, Universidad Nacional Autónoma de México, Facultad de Medicina
• Henry Mead, BioMarin Pharmaceutical Inc.
• Paul V. Lehmann, CASE School of Medicine
• Eli J. Fine, Consultant - Atlanta GA
• Miguel A. Escobar, University of Texas Health Science Center at Houston
• Satish Kumar, University of Texas Rio Grande Valley School of Medicine
• Barbara A. Konkle, University of Washington School of Medicine
• Sarah Williams-Blangero, University of Texas Rio Grande Valley
• et al

Document Type

Article

Publication Date

4-22-2025

Publication Title

Genes and Immunity

Abstract

Hemophilia-A (HA) is the X-linked bleeding disorder caused by heterogeneous factor (F)VIII gene (F8)-mutations and deficiencies in plasma-FVIII-activity that prevent intrinsic-pathway mediated coagulation-amplification. Severe-HA patients (HAPs) require life-long infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called “FVIII-inhibitors (FEIs)”. We investigated the genetics underlying the variable risk of FEI-development in 450 North American HAPs (206 and 244 respectively self-reporting black-African- or white-European-ancestry) by analyzing the genotypes of single-nucleotide-variations (SNVs) in candidate immune-mediated-disease (IMD)-genes using a binary linear-mixed model of genetic association with baseline-FEI-status, the dependent variable, while simultaneously accounting for their genetic relationships and heterogeneous-F8-mutations to prevent the statistical problem of non-independence. We a priori selected gene-centric-association-scans of pleiotropic-IMD-genes implicated in the development of either ≥2 autoimmune-/autoinflammatory-disorders (AADs) or FEIs and ≥1 AAD. We found that baseline-FEI-status was significantly associated with NOS2A (rs117382854; p = 3.2 × 10−6) and B3GNT2 (rs10176009; p = 5.1 × 10−6)—pleiotropic-IMD-genes known previously to function in anti-microbial-/-tumoral-immunity but not in the development of FEIs—and confirmed associations with CTLA4 (rs231780; p = 2.2 × 10−5). We also found that baseline-FEI-status has a substantial heritability (~55%) that involves (i) a F8-mutation-specific component of ~8%, (ii) an additive-genetic contribution from SNVs in IMD-genes of ~47%, and (iii) race, which is a significant determinant independent of F8-mutation-types and non-F8-genetics.

PubMed ID

40999024

Comments

See article for full author list.

Correction to article published September 25, 2025. Original Article DOI: https://doi.org/10.1038/s41435-025-00325-7

Rights

© 2025 Springer Nature Limited

Recommended Citation

Almeida, Marcio A.; Diego, Vincent P.; Viel, Kevin R.; Luu, Bernadette W.; Haack, Karin; Rajalingam, Raja; Ameri, Afshin; Chitlur, Meera; Rydz, Natalia; Lillicrap, David; Watts, Raymond G.; Kessler, Craig M.; Ramsey, Christopher; Dinh, Long V.; Kim, Benjamin; Powell, Jerry S.; Manusov, Eron G.; Peralta, Juan M.; Bouls, Ruayda; Abraham, Shirley M.; Shen, Yu Min; Murillo, Carlos M.; Mead, Henry; Lehmann, Paul V.; Fine, Eli J.; Escobar, Miguel A.; Kumar, Satish; Konkle, Barbara A.; Williams-Blangero, Sarah; and al, et, "A scan of pleiotropic immune mediated disease genes identifies novel determinants of baseline FVIII inhibitor status in hemophilia A" (2025). School of Medicine Faculty Publications. 3692.
https://digitalscholar.lsuhsc.edu/som_facpubs/3692
10.1038/s41435-025-00325-7