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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:214-218.)
© 1995 American Heart Association, Inc.

Articles

Genotypic Variation in the Promoter Region of the Protein C Gene Is Associated With Plasma Protein C Levels and Thrombotic Risk

C. Arnold Spek; Ted Koster; Frits R. Rosendaal; Rogier M. Bertina; Pieter H. Reitsma

From the Hemostasis and Thrombosis Research Center (C.A.S., F.R.R., R.M.B., P.H.R.) and the Department of Clinical Epidemiology (T.K., F.R.R.), University Hospital Leiden, the Netherlands.

Correspondence to C.A. Spek, Hemostasis and Thrombosis Research Center, Department of Hematology, Bldg 1, C2-R University Hospital, PO Box 9600, 2300 CR Leiden, the Netherlands.

Abstract 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).

Key Words: protein C • polymorphism • promoter regions • venous thrombosis • risk factors

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