Association of Sequence Variations in Vitamin K Epoxide Reductase and γ-Glutamyl Carboxylase Genes with Biochemical Measures of Vitamin K Status

Abstract

Summary Genetic factors, specifically the VKORC1 and GGCX genes, have been shown to contribute to the interindividual variability in response to the vitamin K-antagonist, warfarin, which influences the dose required to achieve the desired anticoagulation response. These differences in warfarin sensitivity may be explained by differences in vitamin K status. Men and women (n = 416, 60–80 y), primarily of European descent, were genotyped for common polymorphisms in VKORC1 and GGCX. Cross-sectional associations exist between polymorphisms and biochemical markers of vitamin K [plasma phylloquinone, percent undercarboxylated osteocalcin (%ucOC)]. VKORC1 rs8050894 GG homozygotes had significantly higher cross-sectional measures of plasma phylloquinone than carriers of the CG or CC genotypes (plasma phylloquinone geometric means: GG 0.874±0.092 versus CG/CC 0.598± 0.044; p = 0.020), whereas carriers of VKORC1 rs7294 AA or AG had significantly lower plasma phylloquinone concentrations compared to GG homozygotes (plasma phyllo-quinone geometric means: 0.579±0.045 versus 0.762±0.057; p = 0.035). Cross-sectional analyses also revealed that heterozygous carriers of GGCX rs10187424 and rs7568458 had significantly lower %ucOC relative to either homozygous group. Polymorphisms in genes encoding enzymes involved in vitamin K metabolism may modulate plasma concentrations of phylloquionone and percent carboxylation of osteocalcin.

Sequence Variation in Vitamin K Epoxide Reductase Gene Is Associated With Survival and Progressive Coronary Calcification in Chronic Kidney Disease

“…The allele frequencies were similar to the allele frequencies reported by Crosier et al 22 in individuals aged >60 years in the United States who were also primarily of European descent. Ninety-eight percent of the enrolled subjects were white.…”

“…Whereas no significant heritability was reported in 2 biomarkers of vitamin K status in a crosssectional study of almost 2000 subjects, 33 the minor allele G of the identical SNP was associated with higher concentrations 22 Taken together, at the present time, there are insufficient data to support the contention that factors that influence VKORC1 activity potentially modify arterial disease via its chronic impact on peripheral vitamin K status.…”

“…22 Taken together, at the present time, there are insufficient data to support the contention that factors that influence VKORC1 activity potentially modify arterial disease via its chronic impact on peripheral vitamin K status.…”

Phylloquinone Concentrations and the Risk of Vascular Calcification in Healthy Women

“…For example, the minor allele of VKORC1 rs8050894 (G) and the major allele of VKORC1 rs7294 (G) are associated with higher phylloquinone concentrations. 12 These alleles are linked and have been reported to be part of haplotype sequences that are associated with decreased warfarin dose requirements. 13,14 Furthermore, VKORC1 haplotypes that reduce the activity of the VKORC1 enzyme have been shown to be associated with a significant higher risk of vascular calcification in rats 15 and aortic calcification in humans.…”

Association of GGCX gene polymorphism with warfarin dose in atrial fibrillation population in Xinjiang

“…When reduced vitamin K and O 2 existed, GGCX incorporated CO 2 specifically into glutamic acid residues, the γ-carboxylated glutamic acid were produced. The vitamin K 2, 3 - epoxide was also produced [12,13]. Glutamic acid residue containing vitamin K-dependent clotting factor II, VII, IX, X, protein C and protein S should be carboxylated by GGCX to acquire the activity.…”