Haplotypes of VKORC1, NQO1 and GGCX, their effect on activity levels of vitamin K-dependent coagulation factors, and the risk of venous thrombosis

Visser, Marieke C.; Roshani, S.; Rutten, Julie W.; Vlieg, Astrid van Hylckama; Vos, Hans L.; Rosendaal, Frits R.; Reitsma, P. H.

doi:10.1160/th11-05-0339

Cited by 10 publications

(4 citation statements)

References 16 publications

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“…The NQO1 * 2 genotype has been associated with decreased circulating clotting factor levels in patients in antithrombosis clinics in The Netherlands [11] Furthermore, rats carrying the NQO1 * 2 variant were shown to have decreased coagulation ability compared with wild-type rats [37]. Furthermore, in Taiwanese subjects, the NQO1 * 2 genotype was associated with decreased risk of ischemic stroke [12].…”

Section: Discussionmentioning

confidence: 99%

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Effect of NQO1 and CYP4F2 Genotypes on Warfarin Dose Requirements in Hispanic–Americans and African–Americans

et al. 2012

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Aim The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. Patients & methods The following were assessed in a cohort of 260 African–Americans and 53 Hispanic–Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Results Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs. 0.18; p < 0.05) allele frequencies were higher in Hispanic–Americans compared with African–Americans. Multiple regression analysis in the Hispanic–American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African–Americans after adjusting for known genetic and clinical predictors. Conclusion In our cohort of inner-city Hispanic–Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic–Americans.

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Section: Discussionmentioning

confidence: 99%

“…In vitro data have also shown a direct correlation between NQO1 activity and both the enzyme's capacity to reduce vitamin K and the concentration of dicoumarol needed to inhibit NQO1 activity [10]. The NQO1 * 2 allele has also been associated with reduced clotting factor activity and risk for ischemic stroke [11,12]. …”

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confidence: 99%

Effect of NQO1 and CYP4F2 Genotypes on Warfarin Dose Requirements in Hispanic–Americans and African–Americans

et al. 2012

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“…The potential mechanisms by which VKORC1– 1639 G/A and 1173 C/T genetic polymorphisms play a role in warfarin maintenance dose requirement may be explained by that, warfarin exerts its inhibiting effect on vitamin K to form coagulation factors II, VII, IX and X in the liver, and thereby warfarin dose requirement may be related to the genes encoding the related proteins in the vitamin K cycle pathway [ 32 , 33 ]. VKORC1, as a key vitamin K metabolism enzyme, is able to prevent the production of reduced vitamin K, reducing the formation of vitamin K dependent coagulation factors to achieve an anticoagulant effect [ 34 , 35 ]. VKORC1– 1639 G>A, located in the promoter, is capable of regulating the expression of VKORC1, thus may affect the warfarin maintenance dose requirement.…”

Section: Discussionmentioning

confidence: 99%

Effects of VKORC1 Genetic Polymorphisms on Warfarin Maintenance Dose Requirement in a Chinese Han Population

et al. 2015

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BackgroundVKORC1 is reported to be capable of treating several diseases with thrombotic risk, such as cardiac valve replacement. Some single-nucleotide polymorphisms (SNPs) in VKORC1 are documented to be associated with clinical differences in warfarin maintenance dose. This study explored the correlations of VKORC1–1639 G/A, 1173 C/T and 497 T/G genetic polymorphisms with warfarin maintenance dose requirement in patients undergoing cardiac valve replacement.Material/MethodsA total of 298 patients undergoing cardiac valve replacement were recruited. During follow-up, clinical data were recorded. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was applied to detect VKORC1–1639 G/A, 1173 C/T and 497 T/G polymorphisms, and genotypes were analyzed.ResultsCorrelations between warfarin maintenance dose and baseline characteristics revealed statistical significances of age, gender and operation methods with warfarin maintenance dose (all P<0.05). Warfarin maintenance dose in VKORC1–1639 G/A AG + GG carriers was obviously higher than in AA carriers (P<0.001). As compared with patients with TT genotype in VKORC1 1173 C/T, warfarin maintenance dose was apparently higher in patients with CT genotype (P<0.001). Linear regression analysis revealed that gender, operation method, method for heart valve replacement, as well as VKORC1–1639 G/A and 1173 C/T gene polymorphisms were significantly related to warfarin maintenance dose (all P<0.05).ConclusionsVKORC1 gene polymorphisms are key genetic factors to affect individual differences in warfarin maintenance dose in patients undergoing cardiac valve replacement; meanwhile, gender, operation method and method for heart valve replacement might also be correlate with warfarin maintenance dose.

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“…При цьому дослідження, проведені в нідер-ландській та японській популяціях, не виявило асоціації різних гаплотипів генів VKORC1 та GGCX з розвитком венозного тромбозу [25,26]. Зв'язок цих гаплотипів із вмістом вітамін-К-залежних факторів згортання крові знайдений також не був.…”

Section: обговоренняunclassified

ANALYSIS OF γ-GLUTAMYL CARBOXYLASE GENE rs2592551 POLYMORPHISM ASSOCIATION WITH ISCHEMIC ATHEROTHROMBOTIC STROKE

Dubovyk¹,

Harbuzova²,

Obukhova³

et al. 2017

Fiziol Zh

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Haplotypes of VKORC1, NQO1 and GGCX, their effect on activity levels of vitamin K-dependent coagulation factors, and the risk of venous thrombosis

Cited by 10 publications

References 16 publications

Effect of NQO1 and CYP4F2 Genotypes on Warfarin Dose Requirements in Hispanic–Americans and African–Americans

Effect of NQO1 and CYP4F2 Genotypes on Warfarin Dose Requirements in Hispanic–Americans and African–Americans

Effects of VKORC1 Genetic Polymorphisms on Warfarin Maintenance Dose Requirement in a Chinese Han Population

ANALYSIS OF γ-GLUTAMYL CARBOXYLASE GENE rs2592551 POLYMORPHISM ASSOCIATION WITH ISCHEMIC ATHEROTHROMBOTIC STROKE

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