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.


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-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.
Wang
Yibo
Y
Sino-German Laboratory for Molecular Medicine, Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College and National Genome Center, Beijing, People's Republic of China.
Zhang
Weili
W
Zhang
Yuhui
Y
Yang
Yuejin
Y
Sun
Lizhong
L
Hu
Shengshou
S
Chen
Jilin
J
Zhang
Channa
C
Zheng
Yi
Y
Zhen
Yisong
Y
Sun
Kai
K
Fu
Chunyan
C
Yang
Tao
T
Wang
Jianwei
J
Sun
Jing
J
Wu
Haiying
H
Glasgow
Wayne C
WC
Hui
Rutai
R
D000368:Aged; D001019:Aortic Rupture / Q000175:diagnosis / Q000235:genetics; D001158:Arteries; D016022:Case-Control Studies; D003327:Coronary Disease / Q000175:diagnosis / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000502:physiology; D011110:Polymorphism, Genetic; D020521:Stroke / Q000175:diagnosis / Q000235:genetics; D014652:Vascular Diseases / Q000175:diagnosis / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases
D005819:Genetic Markers; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases