Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
B7-2 Antigen / genetics
-
Biomarkers, Pharmacological
-
Blood Coagulation Tests
-
Factor VIII / antagonists & inhibitors
-
Factor VIII / genetics*
-
Factor VIII / metabolism
-
Genotype
-
Germany
-
HLA-DRB1 Chains / genetics
-
Hemophilia A / genetics*
-
Hemophilia A / therapy
-
Humans
-
Interleukin-10 / genetics
-
Multivariate Analysis
-
Mutation
-
Polymorphism, Single Nucleotide / genetics
-
Prospective Studies
-
Risk Assessment / methods*
-
Risk Factors
Substances
-
B7-2 Antigen
-
Biomarkers, Pharmacological
-
HLA-DRB1 Chains
-
Interleukin-10
-
F8 protein, human
-
Factor VIII
Grants and funding
This study was supported by Institut National de la Santé et de la Recherche Médicale (INSERM) and Centre National de la Recherche Scientifique (CNRS). 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-Mry: 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. Sanofi provided support in the form of salaries for author AHM, SciCross AB provided support in the form of salaries for author PD, GlaxoSmithKline provided support in the form of salaries for author JD who also held held stocks/shares in GlaxoSmithKline, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.