Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, PA 15213, USA.
Am J Physiol Lung Cell Mol Physiol. 2012 Apr 15;302(8):L746-54. doi: 10.1152/ajplung.00319.2011. Epub 2012 Jan 20.
Idiopathic pulmonary fibrosis (IPF) is a complex disease with poorly understood etiology. Previously, we reported upregulation of matrix metalloproteinase 7 (MMP7) in both lung and peripheral blood of IPF patients. Here we report evidence for genetic correlation of plasma levels and promoter polymorphisms (rs11568818 and rs11568819) of MMP7 in a well-characterized IPF cohort. Both the AA genotype of rs11568818 and the CT genotype of rs11568819 were found to be significantly associated with higher MMP7 plasma levels. These associations were observed only in IPF patients and not in healthy controls. The G-to-A transition of rs11568818 resulted in a novel binding site for the forkhead box A2 (FOXA2) transcription factor, a key regulator of embryonic lung development and proper function of the mature lung. In vitro, this transition led to increased sensitivity of the MMP7 promoter to FOXA2. In IPF lungs, FOXA2 was localized in the nucleus of epithelial cells that expressed MMP7 in the cytoplasm. These results suggest that increased sensitivity of the polymorphic MMP7 promoter to FOXA2 provides one of the genetic bases for the upregulation of MMP7 in IPF.
特发性肺纤维化（IPF）是一种病因不明的复杂疾病。我们之前报道过 MMP7 在 IPF 患者的肺部和外周血中均上调。在这里，我们报告了 MMP7 血浆水平及其启动子多态性（rs11568818 和 rs11568819）在一个特征明确的 IPF 队列中的遗传相关性的证据。rs11568818 的 AA 基因型和 rs11568819 的 CT 基因型均与 MMP7 血浆水平升高显著相关。这些关联仅在 IPF 患者中观察到，而在健康对照组中未观察到。rs11568818 的 G 到 A 转换导致了叉头框 A2（FOXA2）转录因子的新结合位点，FOXA2 是胚胎肺发育和成熟肺正常功能的关键调节因子。在体外，这种转变导致 MMP7 启动子对 FOXA2 的敏感性增加。在 IPF 肺中，FOXA2 定位于表达 MMP7 的上皮细胞的核内。这些结果表明，多态性 MMP7 启动子对 FOXA2 的敏感性增加为 IPF 中 MMP7 上调提供了遗传基础之一。
