Genetic determinants of activated factor VII-antithrombin plasma levels and mortality in patients with coronary artery disease

Background: Activated factor VII-antithrombin complex (FVIIa-AT) is an indirect plasma biomarker of the interaction between tissue factor (TF) and FVIIa. High FVIIa-AT levels have been associated with an increased risk of mortality. Methods: We investigated the genetic determinants of FVIIa-AT plasma levels by a candidate gene approach in a cohort of 610 subjects with (n = 478) or without (n = 132) angiographically-demonstrated coronary artery disease (CAD). Results: Plasma concentration of FVIIa-AT did not differ between CAD and CAD-free subjects, but predicted the mortality risk in CAD during a median follow-up of 64-months. Among 7 polymorphisms in 4 candidate genes, codifying for FVII, TF, Endothelial Protein C Receptor (EPCR), and Low-density lipoprotein receptor-Related Protein 1 (LRP1), none was associated with CAD. Three of them were independently associated with FVIIa-AT plasma concentration. F3 -603 A > G polymorphism predicted mortality in CAD consistent with the influence on FVIIa-AT levels, with the G allele-carriers having both higher FVIIa-AT concentration (86.4 with 95 %CI 82.4-90.5 versus 76.7 with 95 %CI 71.0-82.8 pM) and higher mortality risk (HR 1.92 with 95 %CI 1.08-3.41) as compared with AA homozygotes. Conversely, the F7 -323 A1/A2, the strongest genetic predictor of FVIIa-AT variability, and EPCR Ser219Gly polymorphisms were associated with FVIIa-AT levels but were not predictive of mortality. Conclusions: Our results indicate that FVIIa-AT plasma levels are influenced by distinct genetic determinants linked to either TF or FVII expression. The heterogeneous association of FVIIa-AT-related polymorphisms with mortality risk in CAD suggests a predominant role of TF expression rather than FVII levels in the setting of secondary cardiovascular prevention.