TAFI gene haplotypes, TAFI plasma levels and future risk of coronary heart disease: the PRIME Study

Objectives: To evaluate the association of throinbin-activatable fibrinolysis inhibitor (TAFI) gene polymorphisms with the risk of coronary heart disease (CHD) and with TAFI levels measured by a newly developed enzyme-linked immunosorbent assay (ELISA) (TAFI-1B1), shown to be a reliable method for detecting quantitative variations in circulating TAFI. Patients/Methods: Six polymorphisms (C-2599G, G-438A, Ala 147Thr, Thr-325IIe, C + 1542G and T + 1583A) were genotyped and baseline plasma concentrations of TAFI were measured in a nested case-control design as part of the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study. Participants from France and Northern Ireland who had developed a CHD event during a 5-year follow-up (n = 321) were compared with 645 population- and age-matched control subjects. Results: In France, the Thr147 allele was more frequent in cases than in controls (0.41 vs. 0.32; P = 0.02), whereas the reverse was observed in Northern Ireland (0.33 vs. 0.38; P = 0.19) (P = 0.01 for interaction). No other polymorphism was associated with CHD risk. Consistent with the results derived from the single-locus analysis, haplotype analysis revealed that the haplotype carrying the Thr147 allele was associated with increased risk of CHD in France while the reverse tended to hold in the Northern Ireland Population. Single-locus and haplotype analyses revealed that two polymorphisms, C-2599G and Ala I 47Thr (or T + 1583A that is in nearly complete association with it), had additive effects on TAFI levels and explained > 18% of TAFI variability. This effect was homogeneous in France and Northern Ireland, and in cases and controls who exhibited similar TAFI levels. Conclusions: Thrombin-activatable fibrinolysis inhibitor gene polymorphisins are strongly associated to plasma TAFI levels, but the relation to CHD risk is less clear.