Vitamin K epoxide reductase genetic polymorphism is associated with venous thromboembolism: results from the EDITH Study

Abstract

Summary. Background: The vitamin K epoxide reductase complex subunit 1 (VKORC1) recycles endogenous vitamin K, a cofactor for vitamin K-dependent coagulation factor synthesis. Common polymorphisms in VKORC1, the gene coding for VKORC1, have been found to affect the dose response to vitamin K antagonists, and to confer an increased risk of vascular diseases in a Chinese population. The aim of this study was to evaluate the association between the VKORC1 1173C > T polymorphism and venous thromboembolism (VTE). Methods: We report the results of a case-control study designed to evaluate interactions between acquired and inherited risk factors of VTE. We studied 439 cases hospitalized with a first venous thromboembolic event that was not related to a major acquired risk factor for VTE, and 439 matched controls. The VKORC1 1173C > T polymorphism was selected for genotyping as the tagging single-nucleotide polymorphism for previously identified VKORC1 haplotypes. Results: The relationship between VTE and the VKORCI 1173C > T polymorphism was consistent with a recessive model. The frequency of the VKORCI TT genotype was lower in cases than in controls. The odds ratio (OR) (95% CI) was 0.62 (0.41-0.94) for the TT genotype as compared to CT/CC genotypes. Adjustment on cardiovascular diseases, body mass index, factor V (FV) and prothrombin gene mutations did not alter the results. Conclusions: In this case-control study, the frequency of the VKORCI TT genotype was lower in patients with VTE than in matched controls. The clinical consequence of these results remains to be determined, but gives new perspectives for exploration of the role of VKORCI polymorphism in the pathogenesis of VTE.

Lack of association between variants in the VKORC1 gene and cerebrovascular or coronary heart disease

“…In conclusion, our case-control study in European patients with CHD and CVD did not show any association between SNP +2255 in VKORC1 and cardiovascular disease, as opposed to findings in a Chinese population [1] and a French study in patients with venous thromboembolism [14]. When comparing the different studies, differences in haplotype and genotype frequencies between ethnic groups are striking [21].…”

“…Also, a replication study in a North American population could not identify an association with arterial or venous thrombosis (including ischemic stroke) [13], while an association was reported in a French population [14]. In light of conflicting results concerning VKORC1 polymorphisms and cardiovascular diseases, we wondered whether these polymorphisms would be associated with CHD and CVD in a European population and additionally with white matter disease (WMD).…”

VKORC1 genetic polymorphism and risk of venous thromboembolism in postmenopausal women: new findings and meta-analysis

“…The limitation of our analysis is related to the lack of statistical power due to the low sample size.The strong association of VTE with VKORC1 genetic polymorphism previously reported in the EDITH study [7] was not replicated in the ESTHER study. Although only primary or idiopathic VTE was investigated in both studies, differences in age and gender distribution, as well as in the selection of controls, could in part explain this discrepancy.…”

“…We recently showed an association between VKORC1 genetic polymorphism and VTE in the case-control EDITH study [7]. Two other studies have failed to confirm any association between VKORC1 and VTE, stroke and coronary heart disease [8,9].…”

“…Finally, to quantify the association of VKORC1 genetic polymorphism with VTE, we combined the data from all relevant studies, including the ESTHER study [7][8][9].…”