Gender differences of polymorphisms in the TF and TFPI genes, as related to phenotypes in patients with coronary heart d
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ORIGINAL CLINICAL INVESTIGATION
Open Access
Gender differences of polymorphisms in the TF and TFPI genes, as related to phenotypes in patients with coronary heart disease and type-2 diabetes Original clinical investigation
Trine B Opstad*1, Alf Åge Pettersen1, Thomas Weiss1, Harald Arnesen1,3 and Ingebjørg Seljeflot1,2,3
Abstract Background: Tissue factor (TF) and its inhibitor tissue factor pathway inhibitor (TFPI) are the main regulators of the initiation of the coagulation process, important in atherothrombosis. In this study we have investigated the frequency of six known TF and TFPI single nucleotide polymorphisms (SNPs) in CHD patients as compared to healthy individuals. These genotypes and the phenotypes (TF, TFPI free and total antigen) were evaluated with special reference to gender and diabetes in the CHD population. Methods: Patients with angiographically verified CHD (n = 1001; 22% women, 20% diabetics), and 204 healthy controls (28% women), were included. The investigated SNPs were: TF -1812C/T and TF -603A/G in the 5'upstream region, TF 5466A/G in intron 2, TFPI -399C/T and TFPI -287T/C in the 5'upstream region and the TFPI -33T/C in intron 7. Results: No significant differences in frequencies between the CHD population and the controls of any polymorphisms were observed. In the CHD population, the TF 5466 A/G SNP were significantly more frequent in women as compared to men (p < 0.001). The TF-1812C/T and the TF-603A/G SNPs were significantly more frequent in women without type2 diabetes compared to those with diabetes (p < 0.018, both), and the heterozygous genotypes were associated with significantly lower TF plasma levels compared to the homozygous genotypes (p < 0.02, both). The TFPI-399C/T and the TFPI-33T/C SNPs were associated with lower and higher TFPI total antigen levels, respectively (p < 0.001, both).
Conclusion: Genetic variations in the TF and TFPI genes seem to be associated with gender and type-2 diabetes, partly affecting their respective phenotypes.
Background Tissue factor (TF) and its endogenous inhibitor, tissue factor pathway inhibitor (TFPI) are the main regulators of the initiation of the coagulation process, important in atherothrombosis. Injury of the vessel wall and rupture of an atherosclerotic plaque lead to exposure of TF to circulating blood, followed by an activation of the haemostatic system. In addition, blood-borne, or soluble TF (TF) from micro particles and monocytes may represent thrombogenic potential [1]. TFPI is the main regulator in the initial step of the coagulation cascade mediated by TF, by * Correspondence: [email protected] 1
Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ulleval, Oslo, Norway Full list of author information is available at the end of the article
binding to coagulation factors Xa, VIIa and TF forming an inactive complex [2,3]. TFPI, mainly produced by the endothelium [4], is predominantly associated with lipoproteins in the blood [2,5] or is endothelial-bound [6], whereas a small porti
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