Red blood cell (RBC) transfusions are of vital importance in patients with sickle cell disease (SCD). However, a major complication of transfusion therapy is alloimmunization. The low-affinity Fcγ receptors, expressed on immune cells, are important regulators of antibody responses. Genetic variation in FCGR genes has been associated with various auto- and alloimmune diseases. The aim of this study was to evaluate the association between genetic variation of FCGR and RBC alloimmunization in SCD. In this case-control study, DNA samples from 2 cohorts of transfused SCD patients were combined (France and The Netherlands). Cases had a positive history of alloimmunization, having received ≥1 RBC unit. Controls had a negative history of alloimmunization, having received ≥20 RBC units. Single nucleotide polymorphisms and copy number variation of the FCGR2/3 gene cluster were studied in a FCGR-specific multiplex ligation-dependent probe amplification assay. Frequencies were compared using logistic regression. Two hundred seventy-two patients were included (130 controls, 142 cases). The nonclassical open reading frame in the FCGR2C gene (FCGR2C.nc-ORF) was strongly associated with a decreased alloimmunization risk (odds ratio [OR] 0.26, 95% confidence [CI] 0.11-0.64). This association persisted when only including controls with exposure to ≥100 units (OR 0.30, CI 0.11-0.85) and appeared even stronger when excluding cases with Rh or K antibodies only (OR 0.19, CI 0.06-0.59). In conclusion, SCD patients with the FCGR2Cnc-ORF polymorphism have over a 3-fold lower risk for RBC alloimmunization in comparison with patients without this mutation. This protective effect was strongest for exposure to antigens other than the immunogenic Rh or K antigens.

中文翻译：

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非经典 FCGR2C 单倍型与镰状细胞病中红细胞同种免疫保护有关

红细胞 (RBC) 输血对镰状细胞病 (SCD) 患者至关重要。然而，输血治疗的一个主要并发症是同种免疫。在免疫细胞上表达的低亲和力 Fcγ 受体是抗体反应的重要调节剂。FCGR 基因的遗传变异与各种自身和同种免疫疾病有关。本研究的目的是评估 FCGR 的遗传变异与 SCD 中 RBC 同种免疫之间的关联。在该病例对照研究中，合并了来自 2 个输血 SCD 患者队列（法国和荷兰）的 DNA 样本。病例有同种免疫阳性史，接受 ≥ 1 个 RBC 单位。对照组的同种免疫接种史为阴性，接受了≥20 个 RBC 单位。FCGR2/3 基因簇的单核苷酸多态性和拷贝数变异在 FCGR 特异性多重连接依赖性探针扩增试验中进行了研究。使用逻辑回归比较频率。共纳入 272 名患者（对照组 130 名，142 例）。FCGR2C 基因中的非经典开放阅读框 (FCGR2C.nc-ORF) 与同种免疫风险降低密切相关（优势比 [OR] 0.26，95% 置信度 [CI] 0.11-0.64）。当仅包括暴露于 100 单位以上的对照时（OR 0.30，CI 0.11-0.85），这种关联仍然存在，并且在仅排除具有 Rh 或 K 抗体的病例时似乎更强（OR 0.19，CI 0.06-0.59）。综上所述，与没有这种突变的患者相比，具有 FCGR2Cnc-ORF 多态性的 SCD 患者的 RBC 同种免疫风险降低了 3 倍以上。这种保护作用对于暴露于除免疫原性 Rh 或 K 抗原以外的抗原时最强。