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

γ-Glutamyl carboxylation, a reaction essential for the activity of vitamin K—dependent proteins, requires the concerted actions of γ-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 genotyped 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 Gln for Arg at amino acid residue 325 (Arg325Gln). 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 γ-carboxylation reaction influence interindividual variation in the activities of protein C and protein S in the general population.

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Correspondence to Rina Kimura or Yoshihiro Kokubo or Kotaro Miyashita or Ryoichi Otsubo or Kazuyuki Nagatsuka or Toshiho Otsuki or Toshiyuki Sakata or Junko Nagura or Akira Okayama or Kazuo Minematsu or Hiroaki Naritomi or Shigenori Honda or Kiyoshi Sato or Hitonobu Tomoike or Toshiyuki Miyata.

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Kimura, R., Kokubo, Y., Miyashita, K. et al. Polymorphisms in Vitamin K—Dependent γ-Carboxylation—Related Genes Influence Interindividual Variability in Plasma Protein C and Protein s Activities in the General Population. Int J Hematol 84, 387–397 (2006). https://doi.org/10.1532/IJH97.06082

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Key words

  • Genetic polymorphism
  • Vitamin K
  • Protein C activity
  • γ-Glutamyl carboxylase
  • Vitamin K epoxide reductase complex subunit 1
  • Calumenin