Genetic determinants of immunogenicity to factor IX during the treatment of haemophilia B

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Genetic determinants of immunogenicity to factor IX during the treatment of haemophilia BS. Saini1,2, N. Hamasaki-Katagiri1, G. S. Pandey1, C. Yanover3, C. Guelcher2, V. L. Simhadri1, S. Dandekar4, M. F. Guerrera2,5, C. Kimchi-Sarfaty1,* andZ. E. Sauna1,*Article first published online: 2 DEC 2014

DOI: 10.1111/hae.12553

© 2014 John Wiley & Sons Ltd

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HaemophiliaEarly View (Online Version of Record published before inclusion in an issue)

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How to CiteSaini, S., Hamasaki-Katagiri, N., Pandey, G. S., Yanover, C., Guelcher, C., Simhadri, V. L., Dandekar, S., Guerrera, M. F., Kimchi-Sarfaty, C. and Sauna, Z. E. (2014), Genetic determinants of immunogenicity to factor IX during the treatment of haemophilia B. Haemophilia. doi: 10.1111/hae.12553

Author Information1

Laboratory of Hemostasis, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

2

Center for Cancer and Blood Disorders, Children's National Health System, Washington, DC, USA

3

Machine Learning for Healthcare and Life Sciences, IBM Research Laboratory, Haifa, Israel

4

Department of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, USA

5

School of Medicine and Health Sciences, George Washington University, Washington, DC, USA

* Correspondence: Chava Kimchi-Sarfaty, Food and Drug Administration, Room 4118, Building 52, 10903 New Hampshire Ave, Silver Spring MD 20993 USA
Tel.: +301 827 0039; fax: +301 402 2780;
e-mail: chava.kimchi-sarfaty@fda.hhs.gov (or)
Zuben E. Sauna, Food and Drug Administration, Room 4120, Building 52, 10903 New Hampshire Ave, Silver Spring MD 20993 USA
Tel.: +240 402 7362; fax: +301 402 2780;
e-mail: zuben.sauna@fda.hhs.gov

Publication HistoryArticle first published online: 2 DEC 2014Manuscript Accepted: 27 AUG 2014Funded byLaboratory of Hemostasis and the Center for Biologics Evaluation and ResearchFood and Drug Administration's Modernization of Science program SEARCH Search Scope All contentPublication titlesIn this journalIn this issue Search String Advanced >Saved Searches > SEARCH BY CITATION Volume: Issue: Page: ARTICLE TOOLSGet PDF (415K)Save to My ProfileE-mail Link to this ArticleExport Citation for this ArticleGet Citation AlertsRequest Permissions AbstractArticleReferencesCited By View Full Article (HTML) Enhanced Article (HTML) Get PDF (415K) Keywords:F9 gene;factor IX;haemophilia B;immunogenicity;inhibitor antibodiesSummary

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.

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