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

Thrombin-activable fibrinolysis inhibitor (TAFI) is a recently described ca rboxypeptidase that is potentially involved in the regulation of fibrinolys is by decreasing plasminogen binding to the fibrin surface. This role makes the TAFI gene a good candidate in atherothrombotic diseases. The great int erindividual 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 T AFI gene were screened for polymorphisms, and their contribution to the var iability of plasma TAFI antigen levels was evaluated. Seven new polymorphis ms are described, 5 in the promoter (C-2599G, -2345 2G/1G, A-1690G, G-1102T , and G-438A) and 2 in the 3'UTR (C+1542G and T+1583A). All these polymorph isms were in strong linkage disequilibrium with each other and with the pre viously 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, se veral combinations remained significantly and independently associated with plasma TAFI Ag levels: C+1542G associated with Ala147Thr, T+1583A, or -234 5 2G/1G explaining 61.6%, 60.2%, and 58.1% of the variance, respectively. T hese findings clearly demonstrate that circulating levels of TAFI are stron gly determined by polymorphic variations in the promoter and the 3'UTR of t he TAFI gene.