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
Rajalingam Raja, 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

40263602

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