title: Allele-specific transactivation of matrix metalloproteinase 7 by FOXA2 and correlation with plasma levels in idiopathic pulmonary fibrosis.
abstract: 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.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, PA 15213, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Richards
authors.forename: Chunghyun
authors.initials: C
authors.lastname: Park
authors.forename: Yiliang
authors.initials: Y
authors.lastname: Chen
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gibson
authors.forename: Y
authors.initials: Y
authors.lastname: Peter Di
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.forename: Moises
authors.initials: M
authors.lastname: Selman
authors.forename: Joseph
authors.initials: J
authors.lastname: Pilewski
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D001665:Binding Sites; D002478:Cells, Cultured; D005260:Female; D020022:Genetic Predisposition to Disease; D051542:Hepatocyte Nuclear Factor 3-beta / Q000097:blood*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000097:blood*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D015854:Up-Regulation
chemical_list: C496502:FOXA2 protein, human; D051542:Hepatocyte Nuclear Factor 3-beta; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7