Abstract
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.
Highlights
Many studies support an important role for genetic factors in rheumatoid arthritis (RA) susceptibility and progression [1]
Whether the best-characterized single nucleotide polymorphisms (SNPs) affecting transcription of the extracellular matrix (ECM) proteases that have been related with joint pathology are associated with RA susceptibility
We looked for evidence of single nucleotide polymorphisms (SNPs) in the genes encoding these ECM proteases that have shown a regulatory effect on their transcription level, most often from reporter gene assays and from electrophoretic mobility-shift assays and in some cases from ex vivo studies
Summary
Many studies support an important role for genetic factors in rheumatoid arthritis (RA) susceptibility and progression [1]. The best known RA genetic factor is the human leukocyte antigen (HLA) gene, where multiple alleles of the DRbeta chain that share a common epitope in the third hypervariable region determine disease susceptibility and severity. Among the many genes that have been studied, only two that encode extracellular matrix (ECM) proteases have been explored [2,3,4,5,6], despite the unequivocal involvement of this family of proteins in RA. The ECM proteases comprise a large family of proteins grouped in several subfamilies, including the matrix metalloproteinases (MMPs), the most extensively studied in RA [7,8,9].
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