Polymorphisms in vitamin K-dependent gamma-carboxylation-related genes influence interindividual variability in plasma protein C and protein S activities in the general population.
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.
Kimura
Rina
R
Research Institute, National Cardiovascular Center, Suita, Osaka, Japan.
Kokubo
Yoshihiro
Y
Miyashita
Kotaro
K
Otsubo
Ryoichi
R
Nagatsuka
Kazuyuki
K
Otsuki
Toshiho
T
Sakata
Toshiyuki
T
Nagura
Junko
J
Okayama
Akira
A
Minematsu
Kazuo
K
Naritomi
Hiroaki
H
Honda
Shigenori
S
Sato
Kiyoshi
K
Tomoike
Hitonobu
H
Miyata
Toshiyuki
T
D000368:Aged; D044466:Asian People; D002135:Calcium-Binding Proteins / Q000235:genetics*; D019735:Carbon-Carbon Ligases / Q000235:genetics*; D005260:Female; D005828:Genetics, Population; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011486:Protein C / Q000032:analysis* / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017293:Protein S / Q000032:analysis* / Q000235:genetics; D020521:Stroke / Q000097:blood / Q000235:genetics; D014812:Vitamin K / Q000235:genetics / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases
C510527:CALU protein, human; D002135:Calcium-Binding Proteins; D011486:Protein C; D017293:Protein S; D014812:Vitamin K; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase