title: The intron-22-inverted F8 locus permits factor VIII synthesis: explanation for low inhibitor risk and a role for pharmacogenomics.
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.
authors.affiliation: Laboratory of Hemostasis, Division of Hematology Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD;
authors.forename: Zuben E
authors.identifier: http://orcid.org/0000-0001-8202-5188
authors.initials: ZE
authors.lastname: Sauna
authors.affiliation: Hematology Section, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD;
authors.forename: Jay N
authors.initials: JN
authors.lastname: Lozier
authors.affiliation: Orthopaedic Hemophilia Treatment Center, Los Angeles, CA; Department of Medicine, Division of Hematology, Keck School of Medicine, University of Southern California, Los Angeles, CA;
authors.forename: Carol K
authors.initials: CK
authors.lastname: Kasper
authors.affiliation: Machine Learning for Healthcare and Life Sciences, IBM Research Laboratory, Haifa, Israel;
authors.forename: Chen
authors.initials: C
authors.lastname: Yanover
authors.affiliation: Department of Medicine and Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC;
authors.forename: Timothy
authors.initials: T
authors.lastname: Nichols
authors.affiliation: 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.
authors.forename: Tom E
authors.initials: TE
authors.lastname: Howard
mesh_terms: D007446:Chromosome Inversion; D005169:Factor VIII / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007438:Introns / Q000235:genetics; D009154:Mutation; D010597:Pharmacogenetics
chemical_list: C427184:recombinant factor VIII SQ; D005169:Factor VIII