Published Online
on March 20, 2006

A more recent version of this article appeared on March 28, 2006

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Submitted on August 1, 2005
Revised on January 18, 2006
Accepted on January 20, 2006

VKORC1 Haplotypes Are Associated With Arterial Vascular Diseases (Stroke, Coronary Heart Disease, and Aortic Dissection)

Yibo Wang BS, Weili Zhang PhD, Yuhui Zhang MD, Yuejin Yang MD, PhD, Lizhong Sun MD, Shengshou Hu MD, Jilin Chen MD, Channa Zhang , Yi Zheng MD, Yisong Zhen PhD, Kai Sun PhD, Chunyan Fu MD, Tao Yang BS, Jianwei Wang BS, Jing Sun BS, Haiying Wu MD, Wayne C. Glasgow PhD, and Rutai Hui MD, PhD^*

From Sino-German Laboratory for Molecular Medicine (Y.W., W.Z., C.Z., Y. Zheng, Y. Zhen, K.S., C.F., T.Y., J.W., J.S., R.H.), Hypertension Division (Y. Zhang, H.W., R.H.), Department of Cardiology (Y.Y., J.C., R.H.), and Department of Cardiovascular Surgery (L.S., S.H), Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and National Genome Center (Beijing); and Division of Basic Medical Sciences (W.C.G.), Mercer University School of Medicine, Macon, Ga.

^* To whom correspondence should be addressed. E-mail: huirutai{at}sglab.org.

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 -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, r²>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--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.

Key words: vitamin K epoxide reductase • haplotypes • stroke • coronary disease • aortic dissection

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