Vitamin K Epoxide Reductase Complex Subunit 1 (VKORC1) Gene Polymorphisms Predict Arterial Stiffness and Serum MGP...

Background/Objectives: Arterial stiffness increases with progressive worsening of renal function and predicts cardiovascular mortality in patients with chronic kidney disease. The effects of vitamin K-dependent proteins in vascular health and the implications of vitamin K epoxide reductase gene (VKORC1) polymorphisms in calcification and warfarin sensitivity are well known, but their roles in arterial stiffness are not known. We investigated the influence of common polymorphisms in this gene (-1639G>A, +1173C>T, +1542G>C, +2255C>T, and +3730G>A) on stiffness and calcification markers in 302 CKD patients. Methods: Blood pressure, aortic pulse wave velocity (aPWV), coronary artery calcification (CAC), and aortic calcification (AC) were assessed together with the total uncarboxylated matrix Gla protein (t-uncMGP). Results: Genotyping subjects for +1542G>C and +3730G>A showed higher genotype-specific aPWV and lower t-uncMGP (p < 0.05). The combined recessive allele model showed a significant stepwise reduction in aPWV (p < 0.005); subjects homozygous for both risk alleles had the highest aPWV compared to those carrying one or none. In a multiple regression model adjusting for age, gender, mean pressure, BMI, and racial group, each +1542G allele and +3730A allele were independently associated with a 0.8 m/s (95% CI 0.09 to 1.57) and 1.0 m/s (95% CI 0.14 to 1.98) elevation of aPWV, respectively. Although serum t-uncMGP levels correlated inversely with CAC score (p < 0.001), VKORC1 genotypes did not. Conclusions: We demonstrated for the first time that VKORC1 polymorphisms (+1542G>C and +3730G>A) influence arterial stiffness and serum t-uncMGP levels in CKD patients. These findings suggest that vitamin K-dependent processes may be important in arterial stiffness, possibly by modulating calcification of the vessel wall.