A Scan of Pleiotropic Immune Mediated Disease Genes Identifies Novel Determinants of Baseline FVIII Inhibitor Status in Hemophilia-A

• Published in: Research square
• Main Authors: Howard, Tom, Almieda, Marcio, Diego, Vincent, Viel, Kevin, Luu, Bernadette, Haack, Karin, Raja, Rajalingam, Ameri, Afshin, Chitlur, Meera, Rydz, Natalia, Lillicrap, David, Watts, Raymond, Kessler, Craig, Ramsey, Christopher, Dinh, Long, Kim, Benjamin, Powell, Jerry, Peralta, Juan, Bouls, Ruayda, Abraham, Shirley, Shen, Yu-Min, Murillo, Carlos, Mead, Henry, Lehmann, Paul, Fine, Eli, Escobar, Miguel, Kumar, Satish, Williams-Blangero, Sarah, Kasper, Carol, Almasy, Laura, Cole, Shelley, Blangero, John, Konkle, Barbara
• Format: Journal Article
• Language: English
• Published: United States 18.10.2023
• Subjects: Race/ethnicity; Autoimmune-/autoinflammatory-disorders; Gene-centric association scan; Immune-mediated diseases; Factor VIII; Factor VIII gene (F8) mutations; Pleiotropic; Candidate gene; Immune-mediated disease genes and gene variants; Hemophilia A; Factor VIII inhibitors

Hemophilia-A (HA) is caused by heterogeneous loss-of-function factor (F)VIII gene ( )-mutations and deficiencies in plasma-FVIII-activity that impair intrinsic-pathway-mediated coagulation-amplification. The standard-of-care for severe-HA-patients is regular infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called "FVIII-inhibitors (FEIs)" and become refractory. We used the PATH study and ImmunoChip to scan immune-mediated-disease (IMD)-genes for novel and/or replicated genomic-sequence-variations associated with baseline-FEI-status while accounting for non-independence of data due to genetic-relatedness and -mutational-heterogeneity. The baseline-FEI-status of 450 North American PATH subjects-206 with black-African-ancestry and 244 with white-European-ancestry-was the dependent variable. The -mutation-data and a genetic-relatedness matrix were incorporated into a binary linear-mixed model of genetic association with baseline-FEI-status. We adopted a gene-centric-association-strategy to scan, as candidates, pleiotropic-IMD-genes implicated in the development of either ³2 autoimmune-/autoinflammatory-disorders (AADs) or ³1 AAD and FEIs. Baseline-FEI-status was significantly associated with SNPs assigned to (rs117382854; p=3.2E-6) and (rs10176009; p=5.1E-6), which have functions in anti-microbial-/-tumoral-immunity. Among IMD-genes implicated in FEI-risk previously, we identified strong associations with assigned SNPs (p=2.2E-5). The -mutation-effect underlies ~15% of the total heritability for baseline-FEI-status. Additive genetic heritability and SNPs in IMD-genes account for >50% of the patient-specific variability in baseline-FEI-status. Race is a significant determinant independent of -mutation-effects and non- -genetics.