TY  - JOUR
A1  - Bachelet, Delphine
A1  - Albert, Thilo
A1  - Mbogning, Cyprien
A1  - Hässler, Signe
A1  - Zhang, Yuan
A1  - Schultze-Straßer, Stephan
A1  - Repessé, Yohann
A1  - Rayes, Julie
A1  - Pavlova, Anna
A1  - Pezeshkpoor, Behnaz
A1  - Liphardt, Kerstin
A1  - Davidson, Julie E.
A1  - Hincelin-Méry, Agnès
A1  - Dönnes, Pierre
A1  - Lacroix-Desmazes, Sébastien
A1  - Königs, Christoph
A1  - Oldenburg, Johannes
A1  - Broët, Philippe
T1  - Risk stratification integrating genetic data for factor VIII inhibitor development in patients with severe hemophilia A
T2  - PLoS one
N2  - 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.
KW  - Phylogenetic analysis
KW  - Human genetics
KW  - Antigens
KW  - Haplotypes
KW  - Hemophilia A
KW  - Blood groups
KW  - Trees
KW  - Decision trees
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/50369
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-503696
SN  - 1932-6203
N1  - 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.
VL  - 14
IS  - (6): e0218258
SP  - 1
EP  - 16
PB  - PLoS
CY  - Lawrence, Kan.
ER  -