Genetic variation in factor VII associated with variation in plasma lipoprotein(a) concentration

Cross-sectional and prospective studies have shown that individuals with high plasma lipoprotein(a) [Lp(a)] concentrations are at increased risk for coronary heart disease. Size polymorphism of the apolipoprotein(a) [apo(a)] glycoprotein accounts for approximately 35% of the variation in plasma Lp(a) concentrations. However, there is no convincing evidence for associations between plasma Lp(a) and common genetic variation outside APO(a), the gene that encodes apo(a). We tested for association of common genetic variation of candidate genes in lipid metabolism and also of F7 with variation of plasma Lp(a) concentrations in Alberta Hutterites. Variation at codon 353 of F7 has been associated with variation in the plasma factor VII activity (FVIIc), with the 353Q allele associated with lower FVIIc and the 353R allele associated with higher FVIIc. We found significant associations between variation in plasma concentrations of Lp(a) and both apo(a) isoform size and F7 codon 353 genotype (both P < .0001). The effects on plasma Lp(a) concentration of the alleles at codon 353 were additive. The average effects of the F7 353Q and 353R alleles were, respectively, to decrease by 1.71 micrograms/mL and to increase by 0.301 microgram/mL plasma Lp(a) concentration from the sample mean. This suggests that common genomic variation in F7 is associated with variation in plasma Lp(a) concentration.