Contribution of the-455G/A polymorphism at the beta-fibrinogen gene to erythrocyte aggregation in patients with coronary artery disease

Background. A high level of red blood cell (RBC) aggregation has been consi stently found in patients with coronary artery disease (CAD) in case-contro l studies. Plasma fibrinogen has been shown to promote RBC aggregability. T he purpose of this study was to investigate the influence of the genetic va riability of the P-fibrinogen gene on RBC aggregation in patients with CAD. Methods and Results. The genotype of the beta-fibrinogen gene locus was de termined by polymerase chain reaction using the restriction enzyme HaeIII f or a G to A substitution at position -455 upstream from the transcriptional start site in 135 French Canadians with premature CAD (age: 51 +/- 7 years ). Indices measuring the RBC aggregation kinetics (S-10) and shear resistan ce of the aggregates (gamma S) were obtained by laser reflectometry. Patien ts were separated into groups by using the medians of S-10 and gamma S. Usi ng chi(2) analyses, the distribution of the -455GG, -455GA, and -455AA geno types in the groups with high levels of S-10 (0.43, 0.49, and 0.08) and gam ma S (0.45, 0.49, and 0.06) wen found to be significantly distinct from tho se in the groups with low levels of S-10 (0.67, 0.27, and 0.06; p <0.05) an d gamma S (0.70, 0.23, and 0.07; p <0.01). High levels of RBC aggregation w ere closely associated with the rare -455A allele. Multivariate linear regr ession analyses showed that S-10 was positively correlated with the linear combination of the fibrinogen concentration, age, and the -455G/A genotype (adjusted r = 0.63, p <0.0001). Fibrinogen and age were positive determinan ts, and HDL-cholesterol was a negative predictor of gamma S (adjusted r = 0 .51, p <0.0001). Conclusion. These findings support the hypothesis that RBC hyperaggregation in premature CAD may be associated with the P-fibrinogen -455G/A polymorphism. This association may be explained by a change in the concentration and/or the functional properties of the fibrinogen protein.