VKORC1 haplotypes are associated with arterial vascular diseases (stroke, coronary heart disease, and aortic dissection)

Background - The haplotypes in the gene vitamin K epoxide reductase complex subunit 1 (VKORC1) have been found to affect warfarin dose response through effects on the formation of reduced-form vitamin K, a cofactor for gamma-carboxylation of vitamin K - dependent proteins, which is involved in the coagulation cascade and has a potential impact on atherosclerosis. We hypothesized that VKORC1-dependent effects on the coagulation cascade and atherosclerosis would contribute to susceptibility for vascular diseases. Methods and Results - To test the hypothesis, we studied the association of polymorphisms of VKORC1 with stroke ( 1811 patients), coronary heart disease ( 740 patients), and aortic dissection ( 253 patients) compared with matched controls ( n = 1811, 740, and 416, respectively). Five common noncoding single-nucleotide polymorphisms of VKORC1 were identified in a natural haplotype block with strong linkage disequilibrium (D' > 0.9, r(2) > 0.9), then single-nucleotide polymorphism ( SNP) + 2255 in the block was selected for the association study. We found that the presence of the C allele of the + 2255 locus conferred almost twice the risk of vascular disease ( odds ratio [ OR] 1.95, 95% confidence interval [CI].58 to 2.41, P < 0.001 for stroke; OR 1.72, 95% CI 1.24 to 2.38, P < 0.01 for coronary heart disease; and OR 1.90, 95% CI 1.04 to 3.48, P < 0.05 for aortic dissection). We also observed that subjects with the CC and CT genotypes had lower levels of undercarboxylated osteocalcin ( a regulator for the bone), probably vascular calcification, and lower levels of protein induced in vitamin K absence or antagonism II ( PIVKA-II, a des-gamma-carboxy prothrombin) than those with TT genotypes. Conclusions - The haplotype of VKORC1 may serve as a novel genetic marker for the risk of stroke, coronary heart disease, and aortic dissection.