Allele-specific transactivation of matrix metalloproteinase 7 by FOXA2 and correlation with plasma levels in idiopathic pulmonary fibrosis

作者：Richards Thomas J; Park Chunghyun; Chen Yiliang; Gibson Kevin F; Di Y Peter; Pardo Annie; Watkins Simon C; Choi Augustine M K; Selman Moises; Pilewski Joseph; Kaminski Naftali; Zhang Yingze^*

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2012, 302(8): L746-L754.

DOI：10.1152/ajplung.00319.2011

• biomarker
• single nucleotide polymorphism
• outcome
• genetic basis
• forkhead box A2

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.

• 出版日期2012-4
• 单位郑州大学