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

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.
Competing Interests: D. Bachelet, T. Albert, C. Mbogning, S. H¨assler, Y. Zhang, S. Schultze-Strasser, Y Repesse, J. Rayes, A. Pavlova, B. Pezeshkpoor, K. Liphardt, S. LacroixDesmazes, J. Oldenburg, P. Broët have nothing to declare. At the time of writing J. Davidson was employed by and held stocks/shares in GlaxoSmithKline. A.Hincelin-Mery is employed by Sanofi. P. D¨onnes is an employee of SciCross AB. Dr. K¨onigs reports grants and personal fees from Bayer Vital GmbH for research support and speakers bureau, grants and personal fees from Biotest AG for research support and speakers bureau, grants and personal fees from CSL Behring for research support and speakers bureau, personal fees from Grifols for speakers bureau, grants from Intersero for reasearch support, grants and personal fees from Pfizer for research support and speakers bureau, grants and personal fees from Shire for research support and speakers bureau, grants and personal fees from Sobi for research support and speakers bureau, personal fees from Roche for expert testimony, outside the submitted work. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013)and EFPIA companies. J.E. Davidson, A. Hincelin-Mery: belong to EFPIA (European Federation of Pharmaceutical Industries and Association) member companies in the IMI JU and costs related to their part in the research were carried by the respective companies as in kind contributions under the IMI JU scheme. This does not alter his adherence to PLOS ONE policies on sharing data and materials. All the company-employed authors declare that this does not alter their adherence to PLOS ONE policies on sharing data and materials.