Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk.
Protein C is a vitamin K-dependent zymogen of a serine protease that inhibits blood coagulation by proteolytic inactivation of factors Va and VIIIa. Individuals with protein C deficiency are at risk for thrombophlebitis, deep-vein thrombosis, and pulmonary embolism. Genetic analysis of a number of randomly chosen healthy individuals revealed three polymorphisms, C/T at -654, A/G at -641, and A/T at -476, in the protein C promoter region. To investigate whether these genetic variations associate with the plasma protein C level, we determined the genotype for the three polymorphisms and measured plasma protein C levels in 240 individuals not deficient in protein C. The mean protein C level of these individuals was 103%. Interestingly, individuals with the homozygous CGT genotype (n = 40) had a mean protein C level of 94%, whereas individuals with a homozygous TAA genotype (n = 28) had a mean protein C level of 116%. This difference in mean protein C levels between the CGT and TAA groups (P < .001) could not be explained by environmental factors known to influence protein C levels in the normal population. Plasma factor II and factor X levels did not differ between the two groups, which makes a difference in liver function an unlikely cause. Finally, we tested whether the genotype associated with lower protein C levels is associated with higher thrombotic risks. This analysis showed that compared with the genetic variant associated with higher protein C levels (TT/AA/AA), the genetic variant associated with lower protein C levels (CC/GG/TT genotype) is indeed a risk factor for thrombosis (OR, 1.6; 95% confidence interval, 1.0 to 2.5).
Spek
C A
CA
Hemostasis and Thrombosis Research Center, University Hospital Leiden, The Netherlands.
Koster
T
T
Rosendaal
F R
FR
Bertina
R M
RM
Reitsma
P H
PH
D000368:Aged; D001483:Base Sequence; D016022:Case-Control Studies; D017931:DNA Primers; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011486:Protein C / Q000032:analysis / Q000235:genetics*; D012307:Risk Factors; D013927:Thrombosis / Q000209:etiology / Q000235:genetics*
D017931:DNA Primers; D011486:Protein C