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
- 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.
MetadatenAuthor: | Delphine Bachelet, Thilo Albert, Cyprien Mbogning, Signe Hässler, Yuan Zhang, Stephan Schultze-StraßerORCiDGND, Yohann Repessé, Julie Rayes, Anna Pavlova, Behnaz Pezeshkpoor, Kerstin Liphardt, Julie E. Davidson, Agnès Hincelin-Méry, Pierre Dönnes, Sébastien Lacroix-Desmazes, Christoph KönigsORCiDGND, Johannes OldenburgORCiDGND, Philippe Broët |
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URN: | urn:nbn:de:hebis:30:3-503696 |
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DOI: | https://doi.org/10.1371/journal.pone.0218258 |
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ISSN: | 1932-6203 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/31194850 |
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Parent Title (English): | PLoS one |
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Publisher: | PLoS |
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Place of publication: | Lawrence, Kan. |
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Contributor(s): | Pablo Garcia de Frutos |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2019 |
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Date of first Publication: | 2019/06/13 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Contributing Corporation: | ABIRISK consortium |
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Release Date: | 2019/06/17 |
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Tag: | Antigens; Blood groups; Decision trees; Haplotypes; Hemophilia A; Human genetics; Phylogenetic analysis; Trees |
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Volume: | 14 |
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Issue: | (6): e0218258 |
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Page Number: | 16 |
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First Page: | 1 |
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Last Page: | 16 |
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Note: | Copyright: © 2019 Bachelet et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
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HeBIS-PPN: | 450923886 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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