Genetic Variation of the Fc Gamma Receptor 3B Gene and Association with Rheumatoid Arthritis
Genetic Variation of the Fc Gamma Receptor 3B Gene and Association with Rheumatoid Arthritis
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DOI：
10.1371/journal.pone.0013173
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发表时间：
2010-10-05
期刊：
影响因子：
3.7
通讯作者：
Toes, Rene E.
中科院分区：
文献类型：
--
作者：
Marques, Rute B.;Thabet, Mohamed M.;Toes, Rene E.
背景：Fc-γ受体(Fc-Gamma Rs)通过将免疫球蛋白抗体介导的免疫应答与细胞效应和调节功能联系起来，在免疫中发挥重要作用。这些受体的遗传变异此前已被确定为几种慢性炎症的危险因素。本研究旨在探讨FCGR3B基因拷贝数变异(CNV)的存在及其与自身免疫性疾病类风湿关节炎(RA)的关系。方法：采用多重连接依赖探针扩增(MLPA)技术，对518例荷兰RA患者和304例健康对照进行了FCGR3B基因CNV的检测。令人惊讶的是，针对FCGR3B启动子的三个独立的MLPA探针测量到了不同的CNV频率，探针#1和#2测量了0到5个基因拷贝，而探针#3几乎没有显示CNV的证据。定量-聚合酶链式反应与MLPA探针2的拷贝数结果相关，在6.7%的对照人群中检测到低拷贝数(1拷贝)，在9.4%的对照人群中检测到高拷贝数(>；=3拷贝)。RA患者与健康对照组比较，低拷贝数组和高拷贝数组差异均无统计学意义(P值分别为0.36和0.71)。对FCGR3B启动子区域的测序揭示了插入/缺失(INDel)，这解释了MLPA探针#1不同的CNV结果。最后，在新的-256A&>TG INDel与RA之间发现了不显著的趋势(健康对照组40.7%，RA患者35.9%；P=0.08)。结论/意义：本研究突出了FCGR3B基因序列的复杂性和糟糕的特性，表明基于特定探针序列的基因分型分析的设计和解释必须谨慎进行。然而，我们证实了CNV的存在，并在荷兰人群中发现了FCGR3B基因的新的多态。尽管未发现RA与FCGR3B CNV之间的关联，但-256A>；TG indel多态可能的保护作用必须在更大规模的研究中加以解决。
Background: Fc gamma receptors (Fc gamma Rs) play a crucial role in immunity by linking IgG antibody-mediated responses with cellular effector and regulatory functions. Genetic variants in these receptors have been previously identified as risk factors for several chronic inflammatory conditions. The present study aimed to investigate the presence of copy number variations (CNVs) in the FCGR3B gene and its potential association with the autoimmune disease rheumatoid arthritis (RA).Methodology/Principal Findings: CNV of the FCGR3B gene was studied using Multiplex Ligation Dependent Probe Amplification (MLPA) in 518 Dutch RA patients and 304 healthy controls. Surprisingly, three independent MLPA probes targeting the FCGR3B promoter measured different CNV frequencies, with probe#1 and #2 measuring 0 to 5 gene copies and probe#3 showing little evidence of CNV. Quantitative-PCR correlated with the copy number results from MLPA probe#2, which detected low copy number (1 copy) in 6.7% and high copy number (>= 3 copies) in 9.4% of the control population. No significant difference was observed between RA patients and the healthy controls, neither in the low copy nor the high copy number groups (p-values = 0.36 and 0.71, respectively). Sequencing of the FCGR3B promoter region revealed an insertion/deletion (indel) that explained the disparate CNV results of MLPA probe#1. Finally, a non-significant trend was found between the novel -256A>TG indel and RA (40.7% in healthy controls versus 35.9% in RA patients; P = 0.08).Conclusions/Significance: The current study highlights the complexity and poor characterization of the FCGR3B gene sequence, indicating that the design and interpretation of genotyping assays based on specific probe sequences must be performed with caution. Nonetheless, we confirmed the presence of CNV and identified novel polymorphisms in the FCGR3B gene in the Dutch population. Although no association was found between RA and FCGR3B CNV, the possible protective effect of the -256A>TG indel polymorphism must be addressed in larger studies.