title: Genetic determinants of immunogenicity to factor IX during the treatment of haemophilia B.
abstract: Inhibitors are an impediment to the effective management of haemophilia B (HB), but there is limited understanding of the underlying genetic risk factors. In this study we aim to understand the role of F9 gene mutations on inhibitor development in patients with HB. Mutations in the F9 gene were identified and HLA typing performed for five boys with severe HB. Data from the CDC Haemophilia B Mutation Project (CHBMP) database were used to assess association between F9 gene mutation type and inhibitor development. Analysis of the CHBMP database showed that larger disruptions in the F9 gene are associated with a higher life-time prevalence of inhibitors. We detected the following mutations in the five subjects, including four novel mutations: Nonsense in three patients (c.223 C>T; p.Arg75* in two siblings, c.553 C>T; p.Glu185*); Splice site in two patients (c.723 + 1 G>A, c.278-27 A>G); Missense in one patient (c.580 A>G, p.Thr194Ala; c.723 G>T; p.Gln241His). Of the two siblings only one responded to immune tolerance induction (ITI). These siblings have identical F9 gene mutations but differ with respect to the HLA alleles. Interestingly, an analysis of peptide-MHC binding affinities shows a significantly higher (one-sided unpaired t-test, P = 0.0018) median affinity for FIX-derived peptides in the sibling that responded to ITI. We conclude that the nature of the F9 gene mutation may be an important risk factor for the development of inhibitors. In addition, the HLA alleles of the individual patients, in conjunction with the mutation type, could be a predictor for the development of inhibitors as well as the response to ITI.
authors.affiliation: Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.|Center for Cancer and Blood Disorders, Children's National Health System, Washington, DC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Saini
authors.affiliation: Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: N
authors.initials: N
authors.lastname: Hamasaki-Katagiri
authors.affiliation: Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Pandey
authors.affiliation: Machine Learning for Healthcare and Life Sciences, IBM Research Laboratory, Haifa, Israel.
authors.forename: C
authors.initials: C
authors.lastname: Yanover
authors.affiliation: Center for Cancer and Blood Disorders, Children's National Health System, Washington, DC, USA.
authors.forename: C
authors.initials: C
authors.lastname: Guelcher
authors.affiliation: Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: V L
authors.initials: VL
authors.lastname: Simhadri
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dandekar
authors.affiliation: Center for Cancer and Blood Disorders, Children's National Health System, Washington, DC, USA.|School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Guerrera
authors.affiliation: Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Kimchi-Sarfaty
authors.affiliation: Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Z E
authors.initials: ZE
authors.lastname: Sauna
mesh_terms: D000293:Adolescent; D002648:Child; D019295:Computational Biology; D016208:Databases, Factual; D005091:Exons; D005164:Factor IX / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D056726:Genetic Association Studies; D005819:Genetic Markers; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D002836:Hemophilia B / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007518:Isoantibodies / Q000276:immunology*; D008297:Male; D009154:Mutation; D016017:Odds Ratio; D012326:RNA Splicing; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D059811:HLA-DRB1 Chains; D007518:Isoantibodies; D005164:Factor IX
keywords: F9 gene; factor IX; haemophilia B; immunogenicity; inhibitor antibodies