A scan of pleiotropic immune mediated disease genes identifies novel determinants of baseline FVIII inhibitor status in hemophilia A
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
Recommended Citation
Almeida, Marcio A.; Diego, Vincent P.; Viel, Kevin R.; Luu, Bernadette W.; Haack, Karin; Raja, Rajalingam; 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
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