The function and role of F2R polymorphisms in fibroproliferative lung disease.
Doctoral thesis, UCL (University College London).
BACKGROUND: Activation of the coagulation factor II (thrombin) receptor, F2R, by coagulation proteinases contributes to lung inflammation and fibrosis following lung injury. F2R gene expression is raised in fibroproliferative lung disease and F2R-deficient mice are protected in a model of lung inflammation and fibrosis. F2R mRNA expression is highly variable, and its regulation and the role of genetic influences has not been fully characterised. The association of F2R polymorphisms was investigated in sarcoidosis, a highly inflammatory, multisystem disorder in which a proportion of subjects develop lung fibrosis; and the function of F2R promoter haplotypes was explored. METHODS: F2R polymorphisms were genotyped using PCR-based techniques in UK White and Black Afro-Caribbean sarcoidosis subjects and healthy controls. Haplotypes were estimated using PHASE2 software. The function of F2R promoter haplotypes was investigated using dual luciferase reporter gene assays and transfecting in HeLa cells; basally and in response to TNF-\alpha and IL-1\beta. RESULTS: F2R haplotypes associate with sarcoidosis in UK Whites and Black Afro-Caribbeans. This appears to be driven by the rs2227744G>A and rs11267092ins polymorphisms. In reporter gene experiments, basally, the rs2227744A allele alone conferred the highest promoter activity compared with the wild type (2.6 \pm 0.31-fold higher activity, p<0.001). With the rs11267092ins allele alone, promoter activity was 1.3 \pm 0.22-fold higher (p<0.001). Together, the rs2227744A and rs11267092ins alleles increased promoter activity by 1.6 \pm 0.19-fold (p<0.001). There was no response to treatment. DISCUSSION: Both rs2227744G>A and rs11267092ins appear functional. Intriguingly, the rs11267092ins allele appears to interact with the rs2227744G>A allele, reducing the observed increase in promoter activity of the rs2227744G>A allele alone from 2.6 to 1.6-fold. Population studies suggest that rs11267092ins alone and rs11267092ins combined with rs2227744A may be important in sarcoidosis. Elucidating the function and interaction of F2R polymorphisms may help ascertain the mechanism by which F2R contributes to fibroproliferative lung disease.
|Title:||The function and role of F2R polymorphisms in fibroproliferative lung disease|
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