MMP-1 polymorphisms and the risk of idiopathic pulmonary fibrosis
MMP-1 polymorphisms and the risk of idiopathic pulmonary fibrosis
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DOI：
10.1007/s00439-008-0571-z
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发表时间：
2008-12-01
期刊：
影响因子：
5.3
通讯作者：
Pardo, Annie
中科院分区：
文献类型：
--
作者：
Checa, Marco;Ruiz, Victor;Pardo, Annie
特发性肺纤维化（IPF）是一种病因不明、发病机制不明的慢性进行性肺纤维化疾病。基质金属蛋白酶-1（MMP-1）被强烈上调，并可能导致疾病特征的异常重塑。我们对130名IPF患者和305名健康对照者进行了一项病例对照研究，以调查MMP-1基因启动子的两种多态性与IPF风险之间的关系。首先，使用PCR-限制性片段长度多态性（PCR-RFLP）分析，我们研究了-1，607处的2G多态性，先前显示产生AP-1结合位点的核心，并与高转录活性和IPF风险相关。IPF中2G/2G基因型的频率高于对照组（63 vs. 49%; P < 0.008; OR = 1.7; CI 1.15-2.79）。接下来，我们研究了位置-755处的T/G SNP，我们通过对MMP-1启动子进行测序来鉴定。对具有任一-755基因型的IPF成纤维细胞进行的染色质免疫沉淀（ChIP）测定显示TT-755和GT-755基因型的AP-1结合位点。该SNP的频率显示IPF和健康对照之间无显著差异。然而，当研究个体按其吸烟状态分层时，与吸烟对照组相比，吸烟病例中观察到T/T基因型频率显著增加（45%对26%; P = 0.03; OR = 2.3; CI 1.15-4.97）。这些发现表明MMP-1启动子的多态性可能增加IPF的风险，并揭示了MMP-1-755多态性与吸烟之间的假定基因-环境相互作用。
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.