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The Fc gamma receptor IIa R131H polymorphism is associated with inhibitor development in severe hemophilia A

Eckhardt, C. L.; Astermark, Jan LU ; Nagelkerke, S. Q.; Geissler, J.; Tanck, M. W. T.; Peters, M.; Fijnvandraat, K. and Kuijpers, T. W. (2014) In Journal of Thrombosis and Haemostasis 12(8). p.1294-1301
Abstract
Background: The development of factor (F) VIII neutralizing alloantibodies (inhibitors) is a major complication of treatment with FVIII concentrates in hemophilia A and the etiology is still poorly understood. The low-affinity Fc gamma receptors (Fc gamma R), which are expressed on immune cells, provide an important link between cellular and humoral immunity by interacting with IgG subtypes. Genetic variations of the genes encoding Fc gamma Rs (FCGR genes) have been associated with susceptibility to infectious and autoimmune diseases. Objectives: The aim of this study was to investigate the association between genetic variation of FCGR and inhibitor development in severe hemophilia A. Patients/Methods: In this case-control study samples of... (More)
Background: The development of factor (F) VIII neutralizing alloantibodies (inhibitors) is a major complication of treatment with FVIII concentrates in hemophilia A and the etiology is still poorly understood. The low-affinity Fc gamma receptors (Fc gamma R), which are expressed on immune cells, provide an important link between cellular and humoral immunity by interacting with IgG subtypes. Genetic variations of the genes encoding Fc gamma Rs (FCGR genes) have been associated with susceptibility to infectious and autoimmune diseases. Objectives: The aim of this study was to investigate the association between genetic variation of FCGR and inhibitor development in severe hemophilia A. Patients/Methods: In this case-control study samples of 85 severe hemophilia A patients (siblings from 44 families) were included. Single nucleotide polymorphisms and copy number variation of the FCGR2 and FCGR3 gene cluster were studied in an FCGR-specific multiplex ligation-dependent probe amplification assay. Frequencies were compared in a generalized estimating equation regression model. Results: Thirty-six patients (42%) had a positive history of inhibitor development. The polymorphism 131R > H in the FCGR2A gene was associated with an increased risk of inhibitor development (odds ratio [OR] per H-allele, 1.8; 95% confidence interval [CI], 1.1-2.9). This association persisted in 29 patients with high titer inhibitors (OR per H-allele, 1.9; 95% CI, 1.2-3.2) and in 44 patients with the F8 intron 22 inversion (OR per H-allele, 2.6; 95% CI, 1.1-6.6). Conclusions: Hemophilia A patients with the HH genotype of the FCGR2A polymorphism 131R > H have a more than 3-fold increased risk of inhibitor development compared with patients with the RR genotype. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Fc gamma receptors, hemophilia A, neutralizing antibodies, risk factors, single nucleotide polymorphism
in
Journal of Thrombosis and Haemostasis
volume
12
issue
8
pages
1294 - 1301
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000342142700015
  • scopus:84905648933
ISSN
1538-7933
DOI
10.1111/jth.12631
language
English
LU publication?
yes
id
91201d11-cc64-49d3-b543-047ddd54e718 (old id 4709677)
date added to LUP
2014-11-03 07:19:07
date last changed
2017-10-22 03:02:35
@article{91201d11-cc64-49d3-b543-047ddd54e718,
  abstract     = {Background: The development of factor (F) VIII neutralizing alloantibodies (inhibitors) is a major complication of treatment with FVIII concentrates in hemophilia A and the etiology is still poorly understood. The low-affinity Fc gamma receptors (Fc gamma R), which are expressed on immune cells, provide an important link between cellular and humoral immunity by interacting with IgG subtypes. Genetic variations of the genes encoding Fc gamma Rs (FCGR genes) have been associated with susceptibility to infectious and autoimmune diseases. Objectives: The aim of this study was to investigate the association between genetic variation of FCGR and inhibitor development in severe hemophilia A. Patients/Methods: In this case-control study samples of 85 severe hemophilia A patients (siblings from 44 families) were included. Single nucleotide polymorphisms and copy number variation of the FCGR2 and FCGR3 gene cluster were studied in an FCGR-specific multiplex ligation-dependent probe amplification assay. Frequencies were compared in a generalized estimating equation regression model. Results: Thirty-six patients (42%) had a positive history of inhibitor development. The polymorphism 131R > H in the FCGR2A gene was associated with an increased risk of inhibitor development (odds ratio [OR] per H-allele, 1.8; 95% confidence interval [CI], 1.1-2.9). This association persisted in 29 patients with high titer inhibitors (OR per H-allele, 1.9; 95% CI, 1.2-3.2) and in 44 patients with the F8 intron 22 inversion (OR per H-allele, 2.6; 95% CI, 1.1-6.6). Conclusions: Hemophilia A patients with the HH genotype of the FCGR2A polymorphism 131R > H have a more than 3-fold increased risk of inhibitor development compared with patients with the RR genotype.},
  author       = {Eckhardt, C. L. and Astermark, Jan and Nagelkerke, S. Q. and Geissler, J. and Tanck, M. W. T. and Peters, M. and Fijnvandraat, K. and Kuijpers, T. W.},
  issn         = {1538-7933},
  keyword      = {Fc gamma receptors,hemophilia A,neutralizing antibodies,risk factors,single nucleotide polymorphism},
  language     = {eng},
  number       = {8},
  pages        = {1294--1301},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {Journal of Thrombosis and Haemostasis},
  title        = {The Fc gamma receptor IIa R131H polymorphism is associated with inhibitor development in severe hemophilia A},
  url          = {http://dx.doi.org/10.1111/jth.12631},
  volume       = {12},
  year         = {2014},
}