The intron-22-inverted F8 locus permits factor VIII synthesis: explanation for low inhibitor risk and a role for pharmacogenomics.

Zuben E Sauna, Jay N Lozier, Carol K Kasper, Chen Yanover, Timothy Nichols, Tom E Howard

Journal: Blood 2015;125(2):223-8

PMID: 25406352

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Abstract

Intron-22-inversion patients express the entire Factor VIII (FVIII)-amino-acid sequence intracellularly as 2 non-secreted polypeptides and have a positive "intracellular (I)-FVIII-CRM" status. Mutations conferring a positive I-FVIII-CRM status are associated with low inhibitor risk and are pharmacogenetically relevant because inhibitor risk may be affected by the nature of the therapeutic FVIII-protein (tFVIII), the affinity of any tFVIII-derived foreign peptide (tFVIII-fp) for any HLA class-II isomer (HLA-II) comprising individual major histocompatibility complex (MHC) repertoires, and the stability of any tFVIII-fp/HLA-II complex. We hypothesize that mutations conferring a completely or substantially negative I-FVIII-CRM status are pharmacogenetically irrelevant because inhibitor risk is high with any tFVIII and individual MHC repertoire.

Address: Laboratory of Hemostasis, Division of Hematology Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD;; Hematology Section, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD;; Orthopaedic Hemophilia Treatment Center, Los Angeles, CA; Department of Medicine, Division of Hematology, Keck School of Medicine, University of Southern California, Los Angeles, CA;; Machine Learning for Healthcare and Life Sciences, IBM Research Laboratory, Haifa, Israel;; Department of Medicine and Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC;; Department of Pathology and Laboratory Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA; Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA; and Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.

DOI: 10.1182/blood-2013-12-530113