Summary

Activated protein C resistance (APCR) is a major risk factorfor venous thromboembolism (VTE). Although the factor V (FV)Leiden mutation accounts for the vast majority of APCR cases,other polymorphisms may contribute to the APCR phenotype.Genetic components of APCR and thrombophilia were investigatedby two dinucleotide repeats, characterized in introns 2and 11 of the FV gene. Only the intron 11 marker was geneticallystable and thus suitable for further analysis. Its allelic frequencieswere found to differ significantly (P=0.003) betweensubjects selected for increased APCR in the absence of the FVR506Q mutation (n=70, normalized ratios =0.80), and forincreased APC sensitivity (n=98, normalized ratios =1.31).Genotype differences were also found (P=0.017) between FVR506Q heterozygotes (n=100) who had experienced previous VTE and those (n=100), who were still asymptomatic for VTE.Significance was mostly driven by the relative over-representationof the 12R allele and to a minor extent by the under-representationof the 15R allele among the symptomatic versusthe asymptomatic FV Leiden carriers.Two SNPs (4070A/G and 2391A/G) were found to underlie the12R and 15R alleles respectively, and marked extended haplotypes,previously (HR2) or newly (HT2) identified. Only the FVHR2 differed (P=0.002) in frequency between the two groupsof FV R506Q heterozygotes, suggesting that it represents themost relevant FV genetic component of APCR or VTE detectableby this experimental and clinical approach. Our analysisindicates that frequent FV genetic components might contributeto shape the risk for VTE in FV Leiden carriers.