Submitted to: Journal of Nutritional Science and Vitaminology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/17/2008
Publication Date: 4/28/2009
Citation: Crosier, M.D., Peter, I., Booth, S.L., Bennett, G., Dawson-Hughes, B., Ordovas, J.M. 2009. Association of sequence variations in vitamin K epoxide reductase and gamma-glutamyl carboxylas genes with biochemical measures of vitamin K status. Journal of Nutritional Science and Vitaminology. 55:112-119. Interpretive Summary: Genetic factors contribute to the differences among people when comparing how they respond to the vitamin K-antagonist, warfarin. These differences in warfarin sensitivity among individuals may be explained by the role various genes have in influencing vitamin K status. We genotyped 415 older men and women, aged 60 to 80 years and primarily of European descent, for common polymorphisms in two genes that influence vitamin K, VKORC1 and GGCX. We then examined for associations between polymorphisms and biochemical markers of vitamin K. Individuals with the least common polymorphism for VKORC1 had significantly higher vitamin K status than those individuals with the more common polymorphisms. Cross-sectional analyses also revealed that individuals who were heterozygous carriers of GGCX gene may have improved vitamin K function. Polymorphisms in genes encoding enzymes involved in vitamin K metabolism may modulate vitamin K status.
Technical Abstract: 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 between polymorphisms and biochemical markers of vitamin K [plasma phylloquinone, percent under-carboxylated 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 phylloquinone 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 phylloquinone and percent carboxylation of osteocalcin.