Allele-specific transactivation of matrix metalloproteinase 7 by FOXA2 and correlation with plasma levels in idiopathic pulmonary fibrosis
Allele-specific transactivation of matrix metalloproteinase 7 by FOXA2 and correlation with plasma levels in idiopathic pulmonary fibrosis
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DOI：
10.1152/ajplung.00319.2011
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发表时间：
2012-04-01
影响因子：
4.9
通讯作者：
Zhang, Yingze
中科院分区：
文献类型：
--
作者：
Richards, Thomas J.;Park, Chunghyun;Zhang, Yingze
理查兹TJ，Park C，Chen Y，吉布森KF，Di YP，Pardo A，Watkins SC，Choi AMK，Selman M，Pilewski J，Kaminski N，Zhang Y. FOXA 2对基质金属蛋白酶7的等位基因特异性反式激活及其与特发性肺纤维化血浆水平的相关性Am J Physiol Lung Cell Mol Physiol 302：L746-L754，2012.首次发表于2012年1月20日; doi：10.1152/ajplung.00319.2011。特发性肺纤维化（IPF）是一种病因学知之甚少的复杂疾病。以前，我们报道了IPF患者肺和外周血中基质金属蛋白酶7（MMP 7）的上调。在此，我们报告了在一个特征明确的IPF队列中MMP 7的血浆水平和启动子多态性（rs 11568818和rs 11568819）的遗传相关性的证据。研究发现rs 11568818的AA基因型和rs 11568819的CT基因型均与较高的MMP 7血浆水平显著相关。这些关联仅在IPF患者中观察到，而在健康对照中未观察到。rs 11568818的G到A的转换导致了叉头框A2（FOXA 2）转录因子的新结合位点，该转录因子是胚胎肺发育和成熟肺的适当功能的关键调节因子。在体外，这种转变导致MMP 7启动子对FOXA 2的敏感性增加。在IPF肺中，FOXA 2定位于在细胞质中表达MMP 7的上皮细胞的细胞核中。这些结果表明，多态性MMP 7启动子对FOXA 2的敏感性增加为IPF中MMP 7的上调提供了遗传基础之一。
Richards TJ, Park C, Chen Y, Gibson KF, Di YP, Pardo A, Watkins SC, Choi AMK, Selman M, Pilewski J, Kaminski N, Zhang Y. Allele-specific transactivation of matrix metalloproteinase 7 by FOXA2 and correlation with plasma levels in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 302: L746-L754, 2012. First published January 20, 2012; doi:10.1152/ajplung.00319.2011.-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.