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

Authors

Marcio Almeida, The University of Texas Rio Grande ValleyFollow
Vincent P. Diego, The University of Texas Rio Grande ValleyFollow
Kevin R. Viel
Bernadette W. Luu, HaplogenicsFollow
Eron G. Manusov, The University of Texas Rio Grande ValleyFollow
Juan M. Peralta, The University of Texas Rio Grande ValleyFollow
Satish Kumar, The University of Texas Rio Grande ValleyFollow
Sarah Williams-Blangero, The University of Texas Rio Grande ValleyFollow
John Blangero, The University of Texas Rio Grande ValleyFollow
Tom Howard, The University of Texas Rio Grande ValleyFollow

Document Type

Article

Publication Date

6-2025

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.

Comments

Copyright © 2025, The Author(s), under exclusive licence to Springer Nature Limited.

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Recommended Citation

Almeida, M. A., Diego, V. P., Viel, K. R., Luu, B. W., Haack, K., Raja, R., Ameri, A., Chitlur, M., Rydz, N., Lillicrap, D., Watts, R. G., Kessler, C. M., Ramsey, C., Dinh, L. V., Kim, B., Powell, J. S., Manusov, E. G., Peralta, J. M., Bouls, R., … Howard, T. E. (2025). A scan of pleiotropic immune mediated disease genes identifies novel determinants of baseline FVIII inhibitor status in hemophilia A. Genes & Immunity, 26(3), 179–189. https://doi.org/10.1038/s41435-025-00325-7

Publication Title

Genes & Immunity

DOI

10.1038/s41435-025-00325-7

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics