RGD Reference Report - The Fc gamma receptor IIa R131H polymorphism is associated with inhibitor development in severe hemophilia A. - Rat Genome Database

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

Authors: Eckhardt, CL  Astermark, J  Nagelkerke, SQ  Geissler, J  Tanck, MW  Peters, M  Fijnvandraat, K  Kuijpers, TW 
Citation: Eckhardt CL, etal., J Thromb Haemost. 2014 Aug;12(8):1294-301. doi: 10.1111/jth.12631. Epub 2014 Jul 16.
RGD ID: 11040767
Pubmed: PMID:24916518   (View Abstract at PubMed)
DOI: DOI:10.1111/jth.12631   (Journal Full-text)

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 (FcgammaR), 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 FcgammaRs (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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
FCGR2AHumanfactor VIII deficiency susceptibilityIAGP DNA:SNP:cds:p.R131H (human)RGD 
Fcgr2aRatfactor VIII deficiency susceptibilityISOFCGR2A (Homo sapiens)DNA:SNP:cds:p.R131H (human)RGD 
Fcgr3Mousefactor VIII deficiency susceptibilityISOFCGR2A (Homo sapiens)DNA:SNP:cds:p.R131H (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Fcgr2a  (Fc gamma receptor 2A)

Genes (Mus musculus)
Fcgr3  (Fc receptor, IgG, low affinity III)

Genes (Homo sapiens)
FCGR2A  (Fc gamma receptor IIa)


Additional Information