UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Factor VIII cross-matches to the human proteome reduce the predicted inhibitor risk in missense mutation hemophilia A

Hart, DP; Uzun, N; Skelton, S; Kakoschke, A; Househam, J; Moss, DS; Shepherd, AJ; (2019) Factor VIII cross-matches to the human proteome reduce the predicted inhibitor risk in missense mutation hemophilia A. Haematologica , 104 (3) pp. 599-608. 10.3324/haematol.2018.195669. Green open access

[thumbnail of 599.full.pdf]
Preview
Text
599.full.pdf - Published Version

Download (1MB) | Preview

Abstract

Single missense mutations in the F8 gene encoding the coagulation protein factor VIII give rise predominantly to non-severe hemophilia A. Despite only a single amino acid sequence difference between the replacement, therapeutic factor VIII and the patient’s endogenous factor VIII, therapeutic factor VIII may still be perceived as foreign by the recipient’s immune system and trigger an immune response (inhibitor). Inhibitor formation is a life-long risk for patients with non-severe hemophilia A treated with therapeutic factor VIII, but remains difficult to predict. The aim of this study was to understand whether fortuitous, primary sequence cross-matches between therapeutic factor VIII and proteins in the human proteome are the reason why certain F8 mutations are not associated with inhibitor formation. We predicted which therapeutic factor VIII differences are potentially perceived as foreign by helper T cells – a necessary precursor to inhibitor development – and then scanned potentially immunogenic peptides against more than 100,000 proteins in the proteome. As there are hundreds of disease-causing F8 missense mutations and the human leukocyte antigen gene complex governing peptide presentation to helper T cells is highly polymorphic, these calculations pose a huge combinatorial challenge that we addressed computationally. We found that cross-matches between therapeutic factor VIII and the human proteome are commonplace and have a profound impact on the predicted risk of inhibitor development. Our results emphasize the importance of knowing both the F8 missense mutation and the human leukocyte antigen alleles of a patient with missense mutation hemophilia A if his underlying risk of inhibitor development is to be estimated.

Type: Article
Title: Factor VIII cross-matches to the human proteome reduce the predicted inhibitor risk in missense mutation hemophilia A
Open access status: An open access version is available from UCL Discovery
DOI: 10.3324/haematol.2018.195669
Publisher version: https://doi.org/10.3324/haematol.2018.195669
Language: English
Additional information: © 2019 Ferrata Storti Foundation. Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10097001
Downloads since deposit
33Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item