Mutations in the R2 FV gene affect the ratio between the two FV isoforms in plasma

Molecular genetics and biochemical studies were performed in homozygotes fo r the R2 allele (4070G) in the factor V gene, most of them affected by coro nary artery disease. Novel polymorphisms (G642T, 156Ser: T1328C, 385Met/Thr ), among which a functional candidate (A6755G, 2194Asp/Gly) located in the C2 domain of FV, were identified in the R2 gene. In chromatographic studies R2 FV appeared qualitatively identical to normal FV. However, a relative i ncrease of the more thrombogenic and more glycosylated FV isoform (FV1) was observed in plasma of 2194Gly homozygotes (mean FV1/FV2 ratio 0.71, 95% CI 0.66-0.77) as compared to R2-free controls (0.37, 95% Cl 0.34-0.40). We co nclude that carriership of the R2 FV gene is associated with an imbalance b etween the two functionally different FV isoforms, and propose that genetic ally determined differential glycosylation of FV could represent a novel me chanism of thrombotic disease.