Polymorphisms in Vitamin K-Dependent γ-Carboxylation-Related Genes Influence Interindividual Variability in Plasma Protein C and Protein S Activities in the General Population

Abstract

gamma-Glutamyl carboxylation, a reaction essential for the activity of vitamin K-dependent proteins, requires the concerted actions of gamma-glutamyl carboxylase (GGCX), vitamin K 2, 3-epoxide reductase complex 1 (VKORC1), and the chaperone calumenin (CALU). We evaluated the contribution of genetic polymorphisms in VKORC1, GGCX, and CALU to interindividual variation in the activities of plasma protein C and protein S. We sequenced these 3 genes in 96 Japanese individuals and geno-typed 9 representative single-nucleotide polymorphisms in 3655 Japanese individuals representative of the general population. The mean activity of protein C in women bearing the GG genotype of GGCX 8016G>A (130.8% +/- 1.5%, n = 156) was significantly greater (P = .002) than that of individuals with either the AG (126.8% +/- 0.7%, n = 728) or the AA (125.4% +/- 0.6%, n = 881) genotype, after adjusting for confounding factors. The GGCX 8016G>A change leads to the substitution of Gin for Arg at amino acid residue 325 (Arg 325 Gln). This effect was comparable to that of a previously defined polymorphism in the protein C promoter. Mean protein S activity was influenced by the VKORC1 3730G>A and CALU 20943T>A genotypes, after adjusting for confounding factors. Thus, polymorphisms in genes involved in the vitamin K-dependent gamma-carboxylation reaction influence interindividual variation in the activities of protein C and protein S in the general population.

Genetic characterization of antithrombin, protein C and protein S deficiencies in Polish patients

“…16,42,43 PC activity can be modulated also by the genetic variants of EPCR 44 and the polymorphisms of the genes involved in the vitamin K -dependent γ -carboxylation reaction may also influence the activities of PC and PS. 45 It should be also noted that for the measurement of AT activity, both the bovine thrombin-and the FXa inhibition -based tests, together with an antigen method, are advisable to be performed in patients with suspected type II AT deficiency. 46 For thrombin -based tests, a bovine thrombin should be preferred because a human thrombin reacts also with the heparin cofactor II, thus leading to overestimation of AT.…”

Protein C and protein S deficiencies: similarities and differences between two brothers playing in the same game

“…In contrast to these findings, variation at the PROC structural locus did not influence plasma PC concentrations in the GAIT project, but the chromosome region 16q22-23 was found to be a major determinant (67). Polymorphisms in genes involved in the vitamin K dependent g-carboxylation of PC and PS may also be responsible for the inter-individual variation in the plasma concentrations of these proteins in the general population (82).…”

Characterization of calumenin in mouse heart

“…For the calumenin gene, at least 23 single nucleotide polymorphisms (one repeat or one insertion/deletion polymorphism) have been identified in the general population (25). The effect of calumenin polymorphism on the anticoagulant response was also reported (26).…”