title: Genetic modulation of the FV(Leiden)/normal FV ratio and risk of venous thrombosis in factor V Leiden heterozygotes.
abstract: OBJECTIVE
  The factor (F)V Leiden mutation causes activated protein C (APC) resistance by decreasing the susceptibility of FVa to APC-mediated inactivation and by impairing the APC-cofactor activity of FV in FVIIIa inactivation. However, APC resistance and the risk of venous thromboembolism (VTE) vary widely among FV Leiden heterozygotes. Common F5 genetic variation probably contributes to this variability.
  
  
  METHODS
  APC resistance was determined in 250 FV Leiden heterozygotes and 133 normal relatives using the prothrombinase-based assay, which specifically measures the susceptibility of plasma FVa to APC. The effects of 12 F5 single-nucleotide polymorphisms (SNPs) on the normalized APC sensitivity ratio (nAPCsr) and on FV levels were determined by multiple regression analysis.
  
  
  RESULTS
  In FV Leiden heterozygotes,VTE risk increased with increasing nAPCsr, reaching an odds ratio (OR) of 9.9 (95% confidence interval [CI] 1.2–80.5) in the highest nAPCsr quartile. The minor alleles of several F5 SNPs, including 327 A/G (Q51Q), 409 G/C (D79H), 2663 A/G(K830R, T2 haplotype), 6533 T/C (M2120T) and 6755 A/G (D2194G, R2 haplotype), increased the nAPCsr in FV Leiden heterozygotes, but not in their normal relatives. Most of these effects could be attributed to a shift in the FV(Leiden)/normal FV ratio. Four FV Leiden heterozygotes with extremely high nAPCsr turned out to be pseudo-homozygotes, i.e. they carried a deleterious mutation on the non-Leiden allele.
  
  
  CONCLUSIONS
  In FV Leiden heterozygotes, the prothrombinase-based nAPCsr is a marker of VTE risk and is modulated by common F5 SNPs that affect the FV(Leiden)/normal FV ratio in plasma.
authors: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: O
authors: O
authors: Segers
authors: P
authors: P
authors: Simioni
authors: D
authors: D
authors: Tormene
authors: C
authors: C
authors: Bulato
authors: S
authors: S
authors: Gavasso
authors: J
authors: J
authors: Rosing
authors: Elisabetta
authors: E
authors: Castoldi
mesh_terms: D020016:Activated Protein C Resistance / Q000235:genetics*; D015415:Biomarkers; D016022:Case-Control Studies; D005165:Factor V / Q000032:analysis / Q000235:genetics*; D005190:Family; D006579:Heterozygote; D006801:Humans; D050505:Mutant Proteins; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D020246:Venous Thrombosis / Q000209:etiology* / Q000235:genetics
chemical_list: D015415:Biomarkers; D050505:Mutant Proteins; C095381:factor V Leiden; D005165:Factor V