The Fc gamma receptor IIa R131H polymorphism is associated with inhibitor development in severe hemophilia A. (16th July 2014)

• Record Type: Journal Article
• Authors: Eckhardt, C. L.; Astermark, J.; Nagelkerke, S. Q.; Geissler, J.; Tanck, M. W. T.; Peters, M.; Fijnvandraat, K.; Kuijpers, T. W.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 12:Number 8(2014:Aug.)
• Page Start: 1294
• Page End: 1301
• Publication Date: 2014-07-16
• Subjects: Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.12631
• Languages: English
• ISSNs: 1538-7933

Abstract

<abstract abstract-type="main" id="jth12631-abs-0001"> <title>Summary</title> <sec id="jth12631-sec-0001" sec-type="section"> <title>Background</title> <p>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 (FcγR), 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 FcγRs (<italic>FCGR</italic> genes) have been associated with susceptibility to infectious and autoimmune diseases.</p> </sec> <sec id="jth12631-sec-0002" sec-type="section"> <title>Objectives</title> <p>The aim of this study was to investigate the association between genetic variation of <italic>FCGR</italic> and inhibitor development in severe hemophilia A.</p> </sec> <sec id="jth12631-sec-0003" sec-type="section"> <title>Patients/Methods</title> <p>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 <italic>FCGR2</italic> and <italic>FCGR3</italic> gene cluster were studied in an <italic>FCGR</italic>‐specific multiplex ligation‐dependent probe amplification assay. Frequencies were compared in a generalized estimating equation regression model.</p> </sec> <sec id="jth12631-sec-0004" sec-type="section"> <title>Results</title> <p>Thirty‐six patients (42%) had a positive history of inhibitor development. The polymorphism 131R > H in the <italic>FCGR2A</italic> 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 <italic>F8</italic> intron 22 inversion (OR per H‐allele, 2.6; 95% CI, 1.1–6.6).</p> </sec> <sec id="jth12631-sec-0005" sec-type="section"> <title>Conclusions</title> <p>Hemophilia A patients with the HH genotype of the <italic>FCGR2A</italic> polymorphism 131R > H have a more than 3‐fold increased risk of inhibitor development compared with patients with the RR genotype.</p> </sec> </abstract>