Single-nucleotide polymorphisms of matrix metalloproteinase genes are associated with graft fibrosis after kidney transplantation.

ABSTRACT

Background: Further research needs to be conducted on the role of genetic variables in kidney transplantation fibrosis. In this study, we used next-generation sequencing (NGS) to examine the relationship between matrix metalloproteinase (MMP) genes and single-nucleotide polymorphisms (SNPs) in renal allograft fibrosis. Methods: This study comprised 200 patients, whose complete DNA samples were taken. The SNPs in MMP genes were identified using targeted NGS. Hardy-Weinberg equilibrium (HWE) and minor allele frequency (MAF) tests were conducted, followed by a linkage disequilibrium (LD) analysis. Finally, the SNPs and severity of kidney allograft fibrosis were evaluated using different inheritance models. Results: In total, 41 MMP gene-related SNPs were identified using targeted sequencing, and 20 tagger SNPs were retained for further study. The general linear models (GLMs) revealed that sirolimus treatment had a substantial effect on kidney graft fibrosis. The multiple inheritance model analyses revealed that SNP rs9059 of the MMP9 gene was strongly associated with kidney graft fibrosis. The in-vitro experiments showed the MMP9 rs9509 mutation promotes the process of epithelial-mesenchymal transition (EMT) in the human kidney 2 (HK2) cells. Conclusions: The SNP rs9059 is associated with significant kidney allograft pathological changes by promoting EMT progression. Our findings provide insights into the etiology of renal allograft interstitial fibrosis and the MMP9 could be used as a potential treatment target in the future.