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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:200.)
© 2004 American Heart Association, Inc.

Thrombosis

Modulation of Factor V Levels in Plasma by Polymorphisms in the C2 Domain

Daniela Scanavini; Domenico Girelli; Barbara Lunghi; Nicola Martinelli; Cristina Legnani; Mirko Pinotti; Gualtiero Palareti; Francesco Bernardi

From the Department of Biochemistry and Molecular Biology (D.S., B.L., M.P., F.B.), Ferrara University, Italy; Department of Clinical and Experimental Medicine (D.G., N.M.), Verona University, Italy; and Department of Angiology (C.L., G.P.), Unità Ricerca Clinica sulla Trombofilia "Marino Golinelli", University Hospital S. Orsola-Malpighi, Bologna, Italy.

Correspondence to Dr Francesco Bernardi, Department of Biochemistry and Molecular Biology, Ferrara University, via L. Borsari 46, I-44100 Ferrara, Italy. E-mail ber{at}unife.it

Objective— Functional polymorphisms contributing to coagulation factor levels are preferential markers for association studies aimed at identifying prothrombic genetic components.

Methods and Results— Factor V (FV) microsatellite genotypes were found to be associated with FV levels (P=0.003). Single nucleotide polymorphisms analysis and sequencing of the promoter and of coding regions identified two polymorphisms (Met2120Thr, Asp2194Gly) present in 20% of the population (n=1013) that are responsible for genotype-phenotype associations. The effect of the Met2120Thr polymorphism, both in plasma (mean reduction of FV level in the heterozygous condition: 25%) and in recombinant FV studies (34% reduction), was comparable to that of the Asp2194Gly change (20% and 34%, respectively). The study of 10 subjects with a rare genotype indicated that the Asp2194Gly substitution is the functional determinant of the reduced FV levels associated with the FVHR2 haplotype. Among Leiden carriers, the doubly heterozygous condition for FV2120Thr was found to be associated with a significantly increased activated protein-C resistance (APCR) (P<0.05), and the doubly heterozygous condition for FV2194Gly was found to be more frequent (P=0.009) in symptomatic than in asymptomatic subjects.

Conclusions— Extensive analysis of FV polymorphisms indicated that changes in the C2 domain modulate FV levels and might increase APCR and thrombotic risk in FV Leiden carriers through a pseudohomozygous mechanism.

Key Words: factor V levels • functional polymorphisms • FVHR2 haplotype • recombinant FV • APC resistance

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