NEW COAGULATION-FACTOR-V GENE POLYMORPHISMS DEFINE A SINGLE AND INFREQUENT HAPLOTYPE UNDERLYING THE FACTOR-V-LEIDEN MUTATION IN MEDITERRANEAN POPULATIONS AND INDIANS

Two novel polymorphisms were identified in the factor V gene by direct sequencing of intronic areas. One of them, located in intron 9, is th e marker closest to the Leiden mutation ever described, whereas the ot her, in intron 16, displays a rare allele invariantly associated to th e mutation. Allele-specific amplification protocols were designed to p erform extensive screenings for both polymorphic sites. The new marker s were used in combination with six previously described polymorphisms to define specific factor V gene haplotypes. Haplotype investigations in 506Q homozygous thrombotic patients and normal controls showed the presence of a single haplotype underlying the factor V Leiden mutatio n in Mediterranean populations (among which Greek Cypriots, when the R 506Q mutation is particularly frequent) and Indians. When traced in th e absence of the Leiden mutation, the background haplotype was found t o be present and roughly as frequent as the mutation itself in these p opulations. These findings indicate a single mutational event, that pr obably occurred outside Europe, as the cause of the Leiden mutation an d provide a powerful tool to investigate its evolutionary history.