Rodriguez-Lopez Julio, Perez-Pampin Eva, Gomez-Reino Juan J, Gonzalez Antonio
Research Laboratory 2 and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
Arthritis Res Ther. 2006;8(1):R1. doi: 10.1186/ar1849.
Many extracellular matrix (ECM) proteases seem to be important in rheumatoid arthritis (RA) and regulation of their transcription levels is a critical mechanism for controlling their activity. We have investigated, therefore, whether the best-characterized single nucleotide polymorphisms (SNPs) affecting transcription of the ECM proteases that have been related with joint pathology are associated with RA susceptibility. Nine SNPs in eight genes were selected by bibliographic search, including SNPs in the genes encoding matrix metalloproteinase (MMP)1, MMP2, MMP3, MMP7, MMP9, MMP13, plasminogen activator, tissue type (PLAT) and PAI-1. They were studied in a case-control setting that included 550 RA patients and 652 controls of Spanish ancestry from a single center. Genotyping was performed by single-base extension. Only two of the nine SNPs showed significant association with RA susceptibility. RA patients showed increased frequencies of the -7351 T allele of the gene encoding PLAT (36.4% versus 32.1% in controls, p = 0.026) and the -1306 T allele of the gene encoding MMP2 (24.5% versus 20.3% in controls, p = 0.013). These two alleles seemed to cooperate according to an additive model with respect to increased RA susceptibility (p = 0.004), and they were the low-expression alleles of the respective SNPs in a PLAT enhancer and the MMP2 promoter. These findings are in agreement with previous data suggesting that these two ECM proteases have a protective role in RA pathology. Confirmation of these associations will be needed to support these hypotheses. The remaining SNPs did not show association, either individually or collectively. Therefore, although regulatory SNPs in ECM proteases did not show any major effect on RA susceptibility, it was possible to find modest associations that, if replicated, will have interesting implications in the understanding of RA pathology.
许多细胞外基质（ECM）蛋白酶似乎在类风湿性关节炎（RA）中起重要作用，调节其转录水平是控制其活性的关键机制。因此，我们研究了影响与关节病理相关的ECM蛋白酶转录的最具特征的单核苷酸多态性（SNP）是否与RA易感性相关。通过文献检索在八个基因中选择了九个SNP，包括编码基质金属蛋白酶（MMP）1、MMP2、MMP3、MMP7、MMP9、MMP13、组织型纤溶酶原激活剂（PLAT）和PAI-1的基因中的SNP。在一项病例对照研究中对它们进行了研究，该研究包括来自单一中心的550名RA患者和652名西班牙裔对照。通过单碱基延伸进行基因分型。九个SNP中只有两个与RA易感性显著相关。RA患者中编码PLAT的基因的-7351 T等位基因频率增加（对照组为32.1%，患者组为36.4%，p = 0.026），以及编码MMP2的基因的-1306 T等位基因频率增加（对照组为20.3%，患者组为24.5%，p = 0.013）。就增加的RA易感性而言，这两个等位基因似乎根据加性模型协同作用（p = 0.004），并且它们是PLAT增强子和MMP2启动子中各自SNP的低表达等位基因。这些发现与先前的数据一致，表明这两种ECM蛋白酶在RA病理中具有保护作用。需要对这些关联进行验证以支持这些假设。其余的SNP无论是单独还是集体都未显示出关联。因此，尽管ECM蛋白酶中的调节性SNP对RA易感性没有显示出任何主要影响，但有可能发现适度的关联，如果得到重复验证，将对理解RA病理具有有趣的意义。
