Papafili, Anastasia; (2004) Characterisation of a novel variant in the human cyclooxygenase-2 gene: Implications for fibrotic lung disease and inflammation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cyclooxygenase-2 (COX-2) is an inducible enzyme with key regulatory roles in both inflammatory and homeostatic processes. It is therefore not surprising that dysregulated expression of COX-2 often leads to disease. In pulmonary fibrosis, a decreased capacity to upregulate COX-2 occurs despite the increased presence of mediators capable of stimulating its synthesis. The cause of this failure is unknown but may partly be explained by sequence variants in the regulatory regions of COX-2 that modify gene expression. The central focus of this thesis is to identify sequence variants in the proximal promoter of the COX-2 gene, assess their functionality and test for association with interstitial lung diseases such as idiopathic pulmonary fibrosis and sarcoidosis. This thesis describes the identification and characterisation of a novel G to a C substitution in the promoter of the COX-2 gene, at position -765 (-765G>C) upstream of the transcription start site, that is carried by 25% of a healthy UK Caucasian population. Population studies showed that carriage of the rare -765C allele associates with a significant risk for sarcoidosis subjects (OR=1.88 [95% CI 1.26-2.82], P=0.002). Transient transfection of COX-2 promoter constructs in human lung fibroblasts showed that -765G>C represses gene expression. The -765G>C variant locates within a putative binding site for the transcription factor Sp1. DNA- protein binding studies revealed that the transcription factors Spl, Sp3 and Egr-1 bind to that region and that the -765C allele disrupts these interactions. An investigation of -765G>C in an in vivo model of inflammation of patients undergoing coronary bypass surgery demonstrated that the magnitude of rise in levels of the acute phase protein C-reactive protein (CRP), is strongly -765G>C genotype dependent. This thesis describes the first functional variant in the human COX-2 gene and suggests that -765G>C may impact on fibrotic lung disease as well as other inflammatory disorders.

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