Medical Inflammation Research, Department of Experimental Medical Science, Lund University, Sweden.
Antioxid Redox Signal. 2012 Jan 1;16(1):71-8. doi: 10.1089/ars.2011.4013. Epub 2011 Aug 23.
The aim of this study was to investigate genetic variants in the gene neutrophil cytosolic factor 1 (NCF1) for association with rheumatoid arthritis (RA). In rodent models, a single-nucleotide polymorphism (SNP) in Ncf1 has been shown to be a major locus regulating severity of arthritis. Ncf1 encodes one of five subunits of the NADPH oxidase complex. In humans the genomic structure of NCF1 is complex, excluding it from genome-wide association screens and complicating genetic analysis. In addition to copy number variation of NCF1, there are also two nonfunctional pseudogenes, nearly identical in sequence to NCF1. We have characterized copy number variation and SNPs in NCF1, and investigated these variants for association with RA.
We find that RA patients are less likely to have an increased copy number of NCF1, 7.6%, compared with 11.6% in controls; p=0.037. We also show that the T-allele of NCF1-339 (rs13447) is expressed in NCF1 and significantly reduces reactive oxygen species production.
This is the first finding of genetic association of NCF1 with RA. The detailed characterization of genetic variants in NCF1 also helps elucidate the complexity of the NCF1 gene.
These data suggest that an increased copy number of NCF1 can be protective against developing RA and add support to previous findings of a role of NCF1 and the phagocyte NADPH oxidase complex in RA pathogenesis.
本研究旨在探讨中性粒细胞胞浆因子 1（NCF1）基因中的遗传变异与类风湿关节炎（RA）的相关性。在啮齿动物模型中，NCF1 中的单核苷酸多态性（SNP）已被证明是调节关节炎严重程度的主要基因座。NCF1 编码 NADPH 氧化酶复合物的五个亚基之一。在人类中，NCF1 的基因组结构复杂，使其无法进行全基因组关联筛查，从而使遗传分析变得复杂。除了 NCF1 的拷贝数变异外，还有两个与 NCF1 序列几乎完全相同的无功能假基因。我们已经对 NCF1 的拷贝数变异和 SNP 进行了特征描述，并研究了这些变异与 RA 的相关性。
我们发现 RA 患者 NCF1 拷贝数增加的可能性较小，为 7.6%，而对照组为 11.6%；p=0.037。我们还表明，NCF1-339（rs13447）的 T 等位基因在 NCF1 中表达，并显著降低活性氧物质的产生。
这是首次发现 NCF1 与 RA 的遗传关联。对 NCF1 中遗传变异的详细特征描述也有助于阐明 NCF1 基因的复杂性。
这些数据表明，NCF1 拷贝数的增加可能对预防 RA 具有保护作用，并进一步支持 NCF1 和吞噬细胞 NADPH 氧化酶复合物在 RA 发病机制中的作用的先前发现。
