Gene-gene and gene polymorphism interactions of PTGS2 and F2R in the inflammatory and fibrotic processes of sarcoidosis.
Lead Research Organisation:
University College London
Department Name: UNLISTED
Abstract
Lung disease is an enormous burden on the health system, accounting for one in five deaths in the United Kingdom. Chronic lung diseases are the third most reported disorder and include sarcoidosis. Approximately 5-15% of patients with sarcoidosis deteriorate and develop a progressive scarring of the lung termed pulmonary fibrosis. Evidence from the host centre suggests that reduced expression of a gene called PTGS2, removes an important inhibitory control which may help prevent lung scarring. The centre has shown that polymorphisms in this gene reduce its expression and that people carrying these polymorphisms are not only at risk of developing sarcoidosis but, of having a poorer outcome. Furthermore, carrying polymorphisms in PTGS2 and another gene, F2R, further increases this risk. If PTGS2 and F2R polymorphisms are truly predictive for poorer outcome in sarcoidosis, we could target subjects at risk of lung scarring earlier for more aggressive therapy. The implications for early treatment are enormous, as at present there is no treatment that can reverse or halt the scarring process. I propose to 1) confirm that PTGS2 and F2R polymorphisms associate with a risk of sarcoidosis and importantly, show whether they truly predict poorer outcome; and 2) investigate the functional consequences of these polymorphisms in this patient group.
Technical Summary
Approximately 5-15% of sarcoidosis patients deteriorate and develop a progressive scarring of the lung, termed pulmonary fibrosis, involving the aberrant deposition of extracellular matrix, notably collagen.
Evidence from the host centre suggests that reduced expression of PTGS2, also known as COX2, in fibrotic lung diseases (including sarcoidosis) removes an important inhibitory control contributing to progressive fibrosis. This includes removal of a negative feedback downregulation of PAR1, whose activation plays a major role in inflammation and fibrosis in response to lung injury.
The failure to up-regulate PTGS2 expression may, in part, be due to the presence of PTGS2 polymorphisms. The host centre has described a polymorphism, -765G>C, in PTGS2 that reduces gene expression and is strongly associated with susceptibility to sarcoidosis and poorer outcome. Polymorphisms have also been reported in the PAR1 gene (known as F2R) and, interestingly, subjects who carry both PTGS2 -765G>C and F2R -506ins have a higher risk of susceptibility to sarcoidosis and an even higher risk of progressive fibrosis.
Whether PTGS2 and F2R polymorphisms are truly prognostic for poorer outcome in sarcoidosis, and have the potential for identifying subjects early in disease who can be targeted for more aggressive or future specific antifibrotic therapy, remains to be shown. The implications for early treatment to improve the health of patients at risk of progressive fibrosis are enormous, as there is currently no therapeutic intervention that can reverse or halt the fibrotic process. These associations also raise questions on the functional role of PTGS2 and F2R polymorphisms in fibrotic lung disease and whether they have additive effects.
I hypothesise that PTGS2 and F2R promoter genotypes combine in their influence and contribute to a poorer prognosis in sarcoidosis through reduced PTGS2 expression and failure to downregulate PAR1.
To address this hypothesis, I propose to confirm that PTGS2 and F2R polymorphisms associate with sarcoidosis using a case-control design study. Furthermore, I will examine if they are truly prognostic for poorer outcome by following newly diagnosed patients over a two year period before classification as persistent or non-persistent disease. I will also investigate the functional consequences of these polymorphisms alone, and in combination, in blood monocytes and alveolar macrophages isolated from these patients, using in vitro techniques to examine their effect on the expression of PTGS2, F2R and genes known to be upregulated by PAR1 signalling, and on the synthesis of PTGS2 derived products, and on collagen turnover in the lung.
Evidence from the host centre suggests that reduced expression of PTGS2, also known as COX2, in fibrotic lung diseases (including sarcoidosis) removes an important inhibitory control contributing to progressive fibrosis. This includes removal of a negative feedback downregulation of PAR1, whose activation plays a major role in inflammation and fibrosis in response to lung injury.
The failure to up-regulate PTGS2 expression may, in part, be due to the presence of PTGS2 polymorphisms. The host centre has described a polymorphism, -765G>C, in PTGS2 that reduces gene expression and is strongly associated with susceptibility to sarcoidosis and poorer outcome. Polymorphisms have also been reported in the PAR1 gene (known as F2R) and, interestingly, subjects who carry both PTGS2 -765G>C and F2R -506ins have a higher risk of susceptibility to sarcoidosis and an even higher risk of progressive fibrosis.
Whether PTGS2 and F2R polymorphisms are truly prognostic for poorer outcome in sarcoidosis, and have the potential for identifying subjects early in disease who can be targeted for more aggressive or future specific antifibrotic therapy, remains to be shown. The implications for early treatment to improve the health of patients at risk of progressive fibrosis are enormous, as there is currently no therapeutic intervention that can reverse or halt the fibrotic process. These associations also raise questions on the functional role of PTGS2 and F2R polymorphisms in fibrotic lung disease and whether they have additive effects.
I hypothesise that PTGS2 and F2R promoter genotypes combine in their influence and contribute to a poorer prognosis in sarcoidosis through reduced PTGS2 expression and failure to downregulate PAR1.
To address this hypothesis, I propose to confirm that PTGS2 and F2R polymorphisms associate with sarcoidosis using a case-control design study. Furthermore, I will examine if they are truly prognostic for poorer outcome by following newly diagnosed patients over a two year period before classification as persistent or non-persistent disease. I will also investigate the functional consequences of these polymorphisms alone, and in combination, in blood monocytes and alveolar macrophages isolated from these patients, using in vitro techniques to examine their effect on the expression of PTGS2, F2R and genes known to be upregulated by PAR1 signalling, and on the synthesis of PTGS2 derived products, and on collagen turnover in the lung.
