Analysis of a T-287C polymorphism in the tissue factor pathway inhibitor gene and identification of a repressor element in the promoter.
Tissue factor pathway inhibitor (TFPI) is the principle regulator of tissue factor induced blood coagulation. The aim of this study was to investigate the potential association of a T-287C polymorphism in the promoter of the TFPI gene, which we described previously, with deep vein thrombosis (DVT) and to analyse its effect on promoter function. Low TFPI levels were shown to be associated with elevated risk of DVT and we present evidence for a possible association between DVT and T-287C. Any association between T-287C and plasma TFPI levels was masked by environmental effects. We studied the TFPI promoter region between bases -1999 and +229 around the transcription start site and the biological effects of the T-287C polymorphism in a human endothelial cell line using a Dual Luciferase-Reporter Gene Assay. Luciferase activity driven by the 2.2 kb TFPI promoter sequence was low for both allelic variants, but levels of expression from the -287C allele were significantly lower than -287T. Truncated TFPI promoter fragments from both alleles generated much higher transcriptional activity, but differences in reporter gene expression between allelic variants were not significant. Our results indicate the presence of potent repressor sequences between -1999 and -345 in the TFPI promoter and suggest that the TFPI T-287C promoter polymorphism might be a risk factor for DVT.
Amini Nekoo
Ali
A
Institute of Integrative and Comparative Biology, Leeds, LS2 9JT, UK. a.nekoo@gmail.com
Iles
David
D
D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D002478:Cells, Cultured; D003001:Cloning, Molecular; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005838:Genotype; D006801:Humans; D008074:Lipoproteins / Q000097:blood / Q000235:genetics*; D008156:Luciferases / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012307:Risk Factors; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA / Q000379:methods; D014158:Transcription, Genetic; D020246:Venous Thrombosis / Q000097:blood / Q000235:genetics*
D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D008156:Luciferases