Influence of variations across the MMP-1 and -3 genes on the serum levels of MMP-1 and -3 and disease activity in rheumatoid arthritis

Abstract

Matrix metalloproteinases (MMPs) are involved in joint destruction in rheumatoid arthritis (RA), and are strongly associated with levels of inflammation. To understand the relationship between MMP-1 and -3 variants and MMP levels in RA, we investigated the genotypic and haplotypic relationships of the MMP-1 and -3 genes with circulating levels of these MMPs. The genotypes of single-nucleotide polymorphisms (SNPs) rs1799750 (1G/2G, MMP-1 promoter), rs495366 (G/A, intergene), rs679620 (A/G, MMP-3 coding region) and rs3025058 (5A/6A, MMP-3 promoter) were determined in 430 RA patients. Each polymorphism was associated with serum levels of MMP-1 (P trend o0.0001 for each SNP), with haplotype 1G-G-A-5A associated with the highest level. The intergenic and MMP-3 SNPs were associated with MMP-1 levels independent of the MMP-1 promoter SNP. The MMP-3 SNPs were associated with serum MMP-3 level (P trend o0.0001 for each SNP), and were each associated with mean time-averaged disease activity (DAS28) in patients followed up for 2 years (P ¼ 0.003). Our findings indicate that several closely linked polymorphisms in the MMP-1-MMP-3 loci have an important role in determining the circulating levels of these MMPs in RA, and that MMP-3 polymorphism is associated with the level of disease activity over time.

Variants within the MMP3 gene and patellar tendon properties in vivo in an asymptomatic population

“…A promoter polymorphism within the MMP3 gene (rs3025058) is also believed to be tightly linked to the rs679620 variant (Beyzade et al 2003;Chen et al 2012;Raleigh et al 2009). Both markers are associated with MMP3 expression levels, notably the rs3025058 5A allele and the rs679620 'A' allele are associated with relatively lower levels of MMP3, and the highest level of pathological activity related to rheumatoid arthritis.…”

Advanced Oxidation Protein Products Induce Inflammatory Response in Fibroblast-Like Synoviocytes through NADPH Oxidase -Dependent Activation of NF-κB

“…MMP-3, also known as a stromelysin-1, has a broader substrate specificity, with activity against type II, III, IV, IX, X and XI collagens, proteoglycans, fibronectin and laminin and is the most widely studied members in RA [15]. MMP-13, which preferentially degrades type II collagen and aggrecan was exclusively expressed in 80-90% patients of RA [36].…”

“…The synovial tissue destruction observed in RA is due to the activation MMPs mainly secreted by FLSs, macrophages and chondrocytes [15]. Increased levels of MMPs in the synovial fluid of patients with RA are capable of virtually degrading all structural proteins present at the joints [16].…”

Polymorphisms of matrix metalloproteinase gene and adiposity indices in European children: results of the IDEFICS study

“…[32][33][34][35] Cheng et al, 36 in a recent GWA study, found an association between SNP rs650108 located in intron 8 of MMP3 with levels of MMP1. Although these two SNPs (rs645419 and rs650108) were not individually associated with adiposity indices in our study, their combination in haplotype 3 with rs646910 provided a stronger association than either SNP alone, suggesting that this haplotype could tag an additional unmeasured functional polymorphism better than either single SNP alone.…”