Polymorphisms in the tissue factor pathway inhibitor gene are not associated with ischaemic stroke

Abstract

The present study aimed to determine whether four previously described polymorphisms found within the tissue factor pathway inhibitor (TFPI) gene are associated with free plasma TFPI levels or with TFPI activity as well as the risk of ischaemic stroke in stroke patients and control individuals. We conducted a case-control study of 162 first-ever ischaemic stroke cases and 170 randomly selected community control individuals. The TFPI genotype was determined for the T-287C, C-399T, Intron 7 C-33T, and Val264Met (G874A) polymorphisms. Free plasma TFPI and TFPI activity were measured during the first 7 days and 3-6 months after the acute stroke event. Free plasma TFPI levels were significantly lowered 3-6 months after stroke compared with levels observed in the patient group during the acute phase of the stroke (mean, 16.3 versus 22.46 ng/ml; P = 0.046) and among the control group (mean, 16.3 versus 22.79 ng/ml; P< 0.0001). Conversely, TFPI activity was significantly up-regulated during the acute phase (mean, 1.30 versus 1.11 U/ml; P = 0.0051) and remained elevated 3-6 months later (mean, 1.28 versus 1.11 U/ml; P = 0.03). The TFPI gene polymorphisms studied were not significantly associated with TFPI levels or activity, nor with the risk of ischaemic stroke. In conclusion, the TFPI activity and concentration in plasma varied significantly after an ischaemic stroke; however, these variations were not found to be due to the presence of any of the genetic mutations analysed in this study. Our results are consistent with the emerging model suggesting the lipoprotein-bound portion of TFPI has a significant influence on coagulation and diseases of haemostasis.

Genetic determinants of tissue factor pathway inhibitor plasma levels

“…Several studies have tested genetic variants in the TFPI gene and its promoter for association with TFPI plasma levels, but with conflicting results (28,(33)(34)(35). In addition, it is unclear whether genes and genetic variants outside of TFPI are associated with TFPI plasma levels in epidemiological studies.…”

“…Sixteen studies were of variants in the TFPI gene, with up to four variants reported in each study (Suppl. Table 3, available online at www.thrombosis-online.com) (8,9,23,24,26,28,29,31,33,34,(43)(44)(45)(46)(47)(48). One study (31), which was of rs10931292, reported insufficient data to be included in the meta-analysis.…”

Hemostasis and Alterations of the Central Nervous System

“…96 The roles that TFPI polymorphisms may play in stroke risk are so far uncertain, and may be population dependent. 97,98 Thrombin generation accompanies the vasculopathy of atherosclerosis in the acute/subacute events in the cerebral microvasculature during ischemic stroke. This has been observed indirectly as an increase in circulating T-AT complexes.…”

Identification of cardiovascular health gene variants related to longevity in a Chinese population

“…Decreased TFPI concentration will increase the risk of venous thromboembolism (VTE) and myocardial infarction (MI) [ 37 , 38 ]. In this study, a total of 6 groups were included to analyze the influence of TFPI rs7586970 T/C variation on the risk of venous thrombosis caused by increased plasma TFPI concentrations [ 6 , 39 – 43 ]. Meta-analysis results showed that among 1829 venous thrombosis patients and normal controls, plasma TFPI concentration was significantly reduced in carriers of the rs7586970 T allele (p=0.03, OR=0.87).…”

“…Previous studies have shown that ADAMTS7 overexpression in chondrocytes upregulates TNF-α [ 28 , 29 ] and activates PDGFR-β enzyme activity. However, rs3825807 G/G genotype in vascular smooth muscle cells reduced their migratory ability, reducing their ability to recognize and phagocytize oxidized LDL (Ox-LDL) to form fatty streaks [ 39 ]. There, we postulated that vascular smooth muscle cells (VSMCs) of centenarians with the ADAMTS7 A variant may migrate into the endothelium of subcutaneous vessels, phagocytize oxidized LDL, stimulate hemichannel opening to release VLDL into the extracellular environment or adjacent cells, contributing to preventing the occurrence of atherosclerosis through the MAPK pathway.…”