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 i nhibits blood coagulation by proteolytic inactivation of factors Va an d VIIIa. Individuals with protein C deficiency are at risk for thrombo phlebitis, deep-vein thrombosis, and pulmonary embolism. Genetic analy sis 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 prote in 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 24 0 individuals not deficient in protein C. The mean protein C level of these individuals was 103%. Interestingly, individuals with the homozy gous CGT genotype (n=40) had a mean protein C level of 94%, whereas in dividuals with a homozygous TAA genotype (n=28) had a mean protein C l evel of 116%. This difference in mean protein C levels between the CGT and TAA groups (P<.001) could not be explained by environmental facto rs known to influence protein C levels in the normal population. Plasm a 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 level s is associated with higher thrombotic risks. This analysis showed tha t compared with the genetic variant associated with higher protein C l evels (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).