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

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

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)L746-L754
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume302
Issue number8
DOIs
StatePublished - Apr 15 2012

Keywords

  • Forkhead box A2
  • Genetic basis
  • Outcome
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Fingerprint

Dive into the research topics of 'Allele-specific transactivation of matrix metalloproteinase 7 by FOXA2 and correlation with plasma levels in idiopathic pulmonary fibrosis'. Together they form a unique fingerprint.

Cite this