Detection of New Polymorphic Markers in the Factor V Gene: Association with Factor V Levels in Plasma

Abstract

SummaryThree novel polymorphisms were found in the repeated region of the large exon 13 of factor V gene, one giving rise to a codon dimorphism (Serl240) and two causing aminoacid substitutions (Hisl299Arg, Leul257Ile). An increasing frequency of the Argl299 (R2 allele) correlated with a decreasing mean plasma factor V activity in the groups of subjects under study, which included 26 unrelated subjects with partial factor V deficiency. Family studies supported the co-inheritance both of low factor V activity and of R2 allele. The reduction of factor V activity associated with the R2 allele was not clinically symptomatic even in the homozygous condition and was characterized by a parallel reduction of antigen in plasma, in which abnormal molecules were not detected. Data suggest that the R2 allele represents a marker in linkage with an unknown defect rather than a functional polymorphism.These studies provide the first evidence of a genetic component in determining factor V levels in plasma and of a genetic linkage between the factor V gene and factor V deficiency. They also define specific haplotypes which are associated with factor V deficiency or with APC resistance (Arg506Gln) and are valuable fools for the study of factor V defects.

Factor V: a combination of Dr Jekyll and Mr Hyde

“…143 This mutation (in the B region) is a marker that cosegregates with several other polymorphisms encoding several amino acid changes in the factor V molecule. [143][144][145][146] It has been reported that individuals carrying the factor V His1299Arg mutation have mild APC resistance and an increase in the risk of venous thrombosis. Thus, this ensemble of polymorphisms represents per se a potential thrombotic risk factor.…”

Geographic and Ethnic Differences in the Prevalence of Thrombophilia

“…The 677C>T mutation in the methylentetrahydrofolate reductase gene (MTHFR 677C>T), which causes a mild hyperhomocysteinemia, is considered to be a risk factor for coronary heart disease (Kluijtmans et al, 1997;Morita et al, 1997), venous thromboembolism and stroke (Frosst et al, 1995;Arruda et al, 1997;Margaglione et al, 1998, Khandanpour et al, 2009, Tug E et al, 2011, but the results are controversial. New polymorphic markers of the FV gene were described in the last years (Lunghi et al, 1996;Bernardi et al,1997;Castoldi et al, 1997;Castoldi, 2000). A specific factor V gene haplotype (HR2) was defined by five restriction polymorphisms in exon 13 and a sequence variation located in exon 16.…”

“…A specific factor V gene haplotype (HR2) was defined by five restriction polymorphisms in exon 13 and a sequence variation located in exon 16. The exon 13 markers include the Rsa I polymorphic site, the rare allele of which (R2) has been previously found to be associated with partial FV deficiency in the Italian population (Lunghi et al, 1996). The nucleotide change 4070 G>A underlying the R2 allele gives rise to an amino acid change His to Arg at position 1299.…”

Inherited and Acquired Thrombophilia in Pregnancy

“…The two amino acid substitutions coded by the haplotype, 1299HisArg and 1736 Met Val also appear to be neutral (Soria et al, 2003). Some data suggest that the R2 allele represent a marker in linkage with an unknown defect rather than a functional polymorphism (Lunghi et al, 1996).…”