Risk stratification integrating genetic data for factor VIII inhibitor development in patients with severe hemophilia A

Delphine Bachelet, Thilo Albert, Cyprien Mbogning, Signe Hassler, Yuan Zhang, Stephan Schultze-Strasser, Yohann Repesse, Julie Rayes, Anna Pavlova, Behnaz Pezeshkpoor, Kerstin Liphardt, Julie E. Davidson, Agnès Hincelin-Mery, Pierre Donnes, Sebastien Lacroix-Desmazes, Christoph Konigs, Johannes Oldenburg, Philippe Broet

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


Replacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were "high risk" F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: A high-risk group for immunogenicity, including patients with positive HLA-DRB1∗15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1∗15 / HLA-DQB1∗02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach.

Original languageEnglish
Article numbere0218258
JournalPLoS ONE
Issue number6
Publication statusPublished - Jun 2019

Bibliographical note

Publisher Copyright:
© 2019 Bachelet et al.

Copyright 2019 Elsevier B.V., All rights reserved.

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology
  • General Agricultural and Biological Sciences
  • General


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