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

Delphine Bachelet; Thilo Albert; Cyprien Mbogning; Signe Hässler; Yuan Zhang; Stephan Schultze-Strasser; Yohann Repessé; Julie Rayes; Anna Pavlova; Behnaz Pezeshkpoor; Kerstin Liphardt; Julie E Davidson; Agnès Hincelin-Méry; Pierre Dönnes; Sébastien Lacroix-Desmazes; Christoph Königs; Johannes Oldenburg; Philippe Broët; ABIRISK consortium

doi:10.1371/journal.pone.0218258

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

PLoS One. 2019 Jun 13;14(6):e0218258. doi: 10.1371/journal.pone.0218258. eCollection 2019.

Authors

Delphine Bachelet¹, Thilo Albert², Cyprien Mbogning¹, Signe Hässler¹, Yuan Zhang¹, Stephan Schultze-Strasser³, Yohann Repessé⁴, Julie Rayes⁵, Anna Pavlova², Behnaz Pezeshkpoor², Kerstin Liphardt², Julie E Davidson⁶, Agnès Hincelin-Méry⁷, Pierre Dönnes⁸, Sébastien Lacroix-Desmazes⁵, Christoph Königs³, Johannes Oldenburg², Philippe Broët^{1

9}; ABIRISK consortium

Affiliations

¹ CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France.
² Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
³ University Hospital Frankfurt, Goethe University, Department of Pediatrics, Molecular Haemostasis and Immunodeficiency, Frankfurt am Main, Germany.
⁴ CHU Caen, Hématologie Biologique, Caen, Caen, France.
⁵ Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
⁶ GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom.
⁷ Sanofi, Chilly-Mazarin, France.
⁸ SciCross AB, Skövde, Sweden.
⁹ AP-HP, Paris-Sud University Hospitals, Villejuif, France.

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.