Dataset Information

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.

SUBMITTER: Richards TJ

PROVIDER: S-EPMC3331579 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Richards Thomas J TJ Park Chunghyun C Chen Yiliang Y Gibson Kevin F KF Peter Di Y Y Pardo Annie A Watkins Simon C SC Choi Augustine M K AM Selman Moises M Pilewski Joseph J Kaminski Naftali N Zhang Yingze Y

American journal of physiology. Lung cellular and molecular physiology 20120120 8

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 highe ...[more]

PMID: 22268124

Similar Datasets

Project description:BACKGROUND:Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play important roles in the turnover of extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study aimed to determine the utility of circulating MMPs and TIMPs in distinguishing patients with IPF from controls and to explore associations between MMPs/TIMPs and measures of disease severity in patients with IPF. METHODS:The IPF cohort (n?=?300) came from the IPF-PRO Registry, an observational multicenter registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6?months. Controls (n?=?100) without known lung disease came from a population-based registry. Generalized linear models were used to compare circulating concentrations of MMPs 1, 2, 3, 7, 8, 9, 12, and 13 and TIMPs 1, 2, and 4 between patients with IPF and controls, and to investigate associations between circulating levels of these proteins and measures of IPF severity. Multivariable models were fit to identify the MMP/TIMPs that best distinguished patients with IPF from controls. RESULTS:All the MMP/TIMPs analyzed were present at significantly higher levels in patients with IPF compared with controls except for TIMP2. Multivariable analyses selected MMP8, MMP9 and TIMP1 as top candidates for distinguishing patients with IPF from controls. Higher concentrations of MMP7, MMP12, MMP13 and TIMP4 were significantly associated with lower diffusion capacity of the lung for carbon monoxide (DLCO) % predicted and higher composite physiologic index (worse disease). MMP9 was associated with the composite physiologic index. No MMP/TIMPs were associated with forced vital capacity % predicted. CONCLUSIONS:Circulating MMPs and TIMPs were broadly elevated among patients with IPF. Select MMP/TIMPs strongly associated with measures of disease severity. Our results identify potential MMP/TIMP targets for further development as disease-related biomarkers.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets