Role of matrix metalloproteinase-9 polymorphisms in basement membrane degradation and pathogenesis of oral submucous fibrosis

Oral submucous fibrosis (OSMF) is regarded as a collagen and collagenase metabolic disorder. Aberrant expression of matrix metalloproteinases (especially MMP-9) plays important role in remodeling of extracellular matrix (ECM) during development of OSMF. Single nucleotide polymorphisms (SNPs) in MMP-9 promoter and coding region have been demonstrated to be associated with several diseases. In this case-control study, 196 controls and 189 OSMF patients were genotyped at four MMP-9 polymorphic sites on −1562C>T, R279Q, P574R and R688Q loci by Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) method to determine the susceptibility to OSMF. The functional effect of SNPs to the development of OSMF was analyzed by studying the expression of MMP-9, collagen type-I and IV in oral biopsy tissues. R279Q SNP was found to be associated with OSMF [OR 1.5, CI (1.04-2.43), p = 0.03]. The 574R and 668Q alleles were significantly associated with early age group at 2.08 (p = 0.007) and 2.12 (p = 0.011) fold risk to OSMF respectively. MDR analysis showed that -1562C>T and R688Q SNPs were in strong synergy (IG = 0.95%, p = 0.0032) with increased risk of OSMF. Genotypic and functional study revealed definitive role of MMP-9 coding SNPs R279Q, P574R and R668Q in the pathogenesis of OSMF with strong predictive and prognostic value to determine OSMF at early stages in the areca chewers. Pathologically, over-expression of MMP-9 leads to decrease in collagen type-IV and epithelial thinning which contribute to basement membrane degradation along with continuous accumulation of collagen type-I enhanced by MMP-9 −1562C>T, R279Q, P574R and R688Q SNPs, resulting into early onset of OSMF.