MMP-1 polymorphisms and the risk of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disorder of unknown etiology and unclear pathogenesis. Matrix metalloproteinase-1 (MMP-1) is strongly upregulated and may contribute to the abnormal remodeling that characterizes the disease. We conducted a case-control study of 130 IPF patients and 305 healthy controls to investigate associations between two polymorphisms of the MMP-1 gene promoter and IPF risk. First, using PCR-restriction fragment length polymorphism (PCR-RFLP) analysis we studied the 2G polymorphism at -1,607, shown previously to generate the core of an AP-1 binding site and correlate with high transcriptional activity and risk for IPF. The frequency of the 2G/2G genotype was higher in IPF than in controls (63 vs. 49%; P < 0.008; OR = 1.7; CI 1.15-2.79). Next, we studied a T/G SNP at position -755, which we identified by sequencing the MMP-1 promoter. Chromatin immunoprecipitation (ChIP) assay performed on IPF fibroblasts with either -755 genotype revealed an AP-1 binding site for TT(-755) and GT(-755) genotypes. The frequency of this SNP revealed no significant differences between IPF and healthy controls. However, when the study individuals were stratified by their smoking status, a significant increase in the T/T genotype frequency was observed in smoking cases compared with smoking controls (45 vs. 26%; P = 0.03; OR = 2.3; CI 1.15-4.97). These findings indicate that polymorphisms of the MMP-1 promoter may confer increased risk for IPF and reveal a putative gene-environment interaction between the -755 MMP-1 polymorphism and smoking in this disease.

Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice

“…MMPs (49,50,53), neutrophil elastase (54,55), and proteinases of the coagulation cascade (56 -60) have all been implicated in the disease. Although the balance of the literature to date indicates a profibrotic action of these particular proteases, we have found that FAP, a serine protease in the DPP family, exerts a protective anti-fibrotic effect in the setting of lung injury.…”

Effect of RAGE polymorphisms on susceptibility to and severity of osteoarthritis in a Han Chinese population: a case-control study

“…PCR products were digested with the respective restriction endonucleases (New England Biolabs, Inc., Ipswich, MA, USA), and the resulting fragments were separated on a 2.5% agarose gel containing 0.5 mg/mL ethidium bromide by electrophoresis at 100 V and visualized under UV light. Primer design was based on published sequences (Jurajda et al, 2002;Jin et al, 2005;Li et al, 2007;Checa et al, 2008;Kalousova et al, 2009;Daborg et al, 2010). The details of the primers, PCR conditions, restriction enzymes, and genotype configurations are shown in …”

Serum biomarkers in idiopathic pulmonary fibrosis

“…A genetic polymorphism in the MMP1 promotor was linked to IPF in smoking individuals [62]. Rosas et al simultaneously analyzed forty-nine different serum markers and found five MMPs among the twelve proteins differentially expressed in serum from patients with IPF.…”