Identification of polymorphisms in the promoter and the 3′ region of the TAFI gene: evidence that plasma TAFI antigen levels are strongly genetically controlled

Abstract

Thrombin-activable fibrinolysis inhibitor (TAFI) is a recently described carboxypeptidase that is potentially involved in the regulation of fibrinolysis by decreasing plasminogen binding to the fibrin surface. This role makes the TAFI gene a good candidate in atherothrombotic diseases. The great interindividual variability of plasma TAFI antigen levels is poorly explained by lifestyle characteristics, thus suggesting its genetic determination. To test this hypothesis, the promoter and the 3-untranslated region of the TAFI gene were screened for polymorphisms, and their contribution to the variability of plasma TAFI antigen levels was evaluated. Seven new polymorphisms are described, 5 in the promoter (C-2599G, ؊2345 2G/1G, A-1690G, G-1102T, and G-438A) and 2 in the 3UTR (C؉1542G and T؉1583A). All these polymorphisms were in strong linkage disequilibrium with each other and with the previously described Ala147Thr polymorphism. They generated 4 main haplotypes, accounting for 80% of all observed haplotypes. In univariate analyses, all polymorphisms were associated with plasma TAFI Ag levels and, individually, contributed to a large fraction of plasma TAFI Ag levels, ranging from 20% to 52%. In a stepwise regression analysis including all polymorphisms, several combinations remained significantly and independently associated with plasma TAFI Ag levels: C؉1542G associated with Ala147Thr, T؉1583A, or ؊2345 2G/1G explaining 61.6%, 60.2%, and 58.1% of the variance, respectively. These findings clearly demonstrate that circulating levels of TAFI are strongly determined by polymorphic variations in the promoter and the 3UTR of the TAFI gene. (Blood. 2001;97:2053-2058

Metabolic Syndrome Accompanied by Hypercholesterolemia Is Strongly Associated With Proinflammatory State and Impairment of Fibrinolysis in Patients With Type 2 Diabetes

“…between individuals and therefore have been believed to be mainly regulated by genotype (17). The mechanism underlying association between elevated plasma TAFI and LDL cholesterol in type 2 diabetic patients remains to be determined.…”

“…PAI is produced mainly by adipose tissues and vascular endothelial cells (21), while TAFI is produced exclusively by the liver (14). Another possibility is that plasma TAFI concentrations may be regulated more strongly by genotype rather than metabolic factors as mentioned above (17).…”

Genetic Determinants of Arterial Thrombosis

“…These polymorphisms are in strong linkage disequilibrium and form 4 main haplotypes. 78 In a multivariate analysis, the Ala147Thr and 1542C/G polymorphisms in combination showed the strongest influence (Ͼ60%) on TAFI level variability; however, the mechanism for this effect is not yet understood. In fact, a recent segregation-linkage analysis suggested that these polymorphisms were only markers in linkage disequilibrium with unidentified TAFI-linked quantitative trait loci.…”

The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI‐antigen levels, clot lysis time and the risk of venous thrombosis

“…Thrombin activatable fibrinolysis inhibitor levels are also genetically determined and the )438 G/A TAFI single nucleotide polymorphism (SNP) in the promoter region (Henry et al, 2001) and the 505 G/A SNP (Henry et al, 2001) and 1040 C/T SNP in the coding region (Brouwers et al, 2001) are associated with TAFI plasma antigen levels. The )438 G/A polymorphism was reported to be associated with an increased risk of developing venous thrombosis (Franco et al, 2001;Zidane et al, 2003).…”