Department of Pediatric Hematology, Immunology and Infectious Diseases, Academic Medical Center, Amsterdam, the Netherlands.
J Thromb Haemost. 2014 Aug;12(8):1294-301. doi: 10.1111/jth.12631. Epub 2014 Jul 16.
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 (FCGR genes) have been associated with susceptibility to infectious and autoimmune diseases.
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.
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).
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.
因子（F）VIII 中和性同种抗体（抑制剂）的产生是甲型血友病患者接受 FVIII 浓缩物治疗的主要并发症，其病因仍知之甚少。低亲和力 Fcγ 受体（FcγR）在免疫细胞上表达，通过与 IgG 亚型相互作用为细胞和体液免疫提供了重要联系。编码 FcγR 的基因（FCGR 基因）的遗传变异与感染性和自身免疫性疾病的易感性有关。
本研究旨在探讨 FCGR 基因遗传变异与重型甲型血友病抑制剂发展之间的关系。
患者/方法：在这项病例对照研究中，纳入了 85 名重型甲型血友病患者（来自 44 个家庭的兄弟姐妹）的样本。使用 FCGR 特异性多重连接依赖性探针扩增检测法研究了 FCGR2 和 FCGR3 基因簇的单核苷酸多态性和拷贝数变异。在广义估计方程回归模型中比较了频率。
36 名患者（42%）有抑制剂发展的阳性病史。FCGR2A 基因中的 131R > H 多态性与抑制剂发展的风险增加相关（每 H 等位基因的优势比[OR]，1.8；95%置信区间[CI]，1.1-2.9）。这种关联在 29 名高滴度抑制剂患者中持续存在（每 H 等位基因的 OR，1.9；95% CI，1.2-3.2）和在 44 名 F8 内含子 22 倒位患者中持续存在（每 H 等位基因的 OR，2.6；95% CI，1.1-6.6）。
与 RR 基因型患者相比，FCGR2A 基因 131R > H 多态性 HH 基因型的甲型血友病患者抑制剂发展的风险增加了 3 倍以上。
