Modulation of factor V levels in plasma by polymorphisms in the C2 domain.
OBJECTIVE
Functional polymorphisms contributing to coagulation factor levels are preferential markers for association studies aimed at identifying prothrombic genetic components.


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.
Scanavini
Daniela
D
Department of Biochemistry and Molecular Biology, Ferrara University, Italy.
Girelli
Domenico
D
Lunghi
Barbara
B
Martinelli
Nicola
N
Legnani
Cristina
C
Pinotti
Mirko
M
Palareti
Gualtiero
G
Bernardi
Francesco
F
D020016:Activated Protein C Resistance / Q000453:epidemiology / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005165:Factor V / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D005166:Factor V Deficiency / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008403:Mass Screening; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D011655:Pulmonary Embolism / Q000453:epidemiology / Q000235:genetics; D013329:Structure-Activity Relationship; D019851:Thrombophilia / Q000453:epidemiology / Q000235:genetics; D020246:Venous Thrombosis / Q000453:epidemiology / Q000235:genetics
C095381:factor V Leiden; D005165:Factor V