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Risk stratification integrating genetic data for factor VIII inhibitor development in patients with severe hemophilia A
CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France.
Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany.
CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France.
CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France.
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 6, article id e0218258Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 14, no 6, article id e0218258
Keywords [en]
class-II, dendritic cells, HLA alleles, polymorphism, interleukin-10, prediction, protects, impact
National Category
Hematology Medical Genetics
Identifiers
URN: urn:nbn:se:his:diva-17651DOI: 10.1371/journal.pone.0218258ISI: 000471238300075PubMedID: 31194850Scopus ID: 2-s2.0-85067866441OAI: oai:DiVA.org:his-17651DiVA, id: diva2:1348881
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ABIRISK consortium

Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-09-11Bibliographically approved

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Dönnes, Pierre

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1011121314151613 of 47
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