Effects of NAD(P)H quinone oxidoreductase 1 polymorphisms on stable warfarin doses in Korean patients with mechanical cardiac valves

Chung, Jee-Eun; Chang, Byung Chul; Lee, Jun Young; Kim, Joo Hee; Gwak, Hye Sun

doi:10.1007/s00228-015-1915-y

Cited by 14 publications

(6 citation statements)

References 26 publications

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“…The rs2364723 (C107G) polymorphism was associated with reduced risk of cardiovascular mortality [ 12 ]. The NQO1 gene polymorphism rs1800566 (C609T) is characterized by the replacement of proline by serine at position number 187 of the functional protein, which causes destabilization and inactivation of the enzyme [ 13 , 14 ]. The rs1800566 polymorphism has been associated with lower levels of blood coagulation factors [ 15 ], higher risk of coronary artery disease in T2DM patients [ 16 , 17 ], and increased triglycerides levels and decreased HDL-C levels in individuals with metabolic syndrome [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Association of Nuclear Factor‐Erythroid 2‐Related Factor 2, Thioredoxin Interacting Protein, and Heme Oxygenase‐1 Gene Polymorphisms with Diabetes and Obesity in Mexican Patients

Jiménez-Osorio

González-Reyes

García-Niño

et al. 2016

Oxidative Medicine and Cellular Longevity

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The nuclear factor-erythroid 2- (NF-E2-) related factor 2 (Nrf2) is abated and its ability to reduce oxidative stress is impaired in type 2 diabetes and obesity. Thus, the aim of this study was to explore if polymorphisms in Nrf2 and target genes are associated with diabetes and obesity in Mexican mestizo subjects. The rs1800566 of NAD(P)H:quinone oxidoreductase 1 (NQO1) gene, rs7211 of thioredoxin interacting protein (TXNIP) gene, rs2071749 of heme oxygenase-1 (HMOX1) gene, and the rs6721961 and the rs2364723 from Nrf2 gene were genotyped in 627 diabetic subjects and 1020 controls. The results showed that the rs7211 polymorphism is a protective factor against obesity in nondiabetic subjects (CC + CT versus TT, OR = 0.40, P = 0.005) and in women (CC versus CT + TT, OR = 0.7, P = 0.016). TT carriers had lower high-density lipoprotein cholesterol levels and lower body mass index. The rs2071749 was positively associated with obesity (AA versus AG + GG, OR = 1.25, P = 0.026). Finally, the rs6721961 was negatively associated with diabetes in men (CC versus CA + AA, OR = 0.62, P = 0.003). AA carriers showed lower glucose concentrations. No association was found for rs1800566 and rs2364723 polymorphisms. In conclusion, the presence of Nrf2 and related genes polymorphisms are associated with diabetes and obesity in Mexican patients.

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Section: Introductionmentioning

confidence: 99%

Association of Nuclear Factor‐Erythroid 2‐Related Factor 2, Thioredoxin Interacting Protein, and Heme Oxygenase‐1 Gene Polymorphisms with Diabetes and Obesity in Mexican Patients

Jiménez-Osorio

González-Reyes

García-Niño

et al. 2016

Oxidative Medicine and Cellular Longevity

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“…Given this evidence and the once putative role of NQO1 in vitamin K recycling, we and others have examined warfarin dose requirements by the NQO1*2 genotype with mixed results. Although no association has been identified in European or African ancestry populations, 19,40 accumulating data suggest an association in some Latino and Asian populations; although data are not entirely consistent 19,22,41,42 …”

Section: Discussionmentioning

confidence: 99%

“…Although no association has been identified in European or African ancestry populations, 19,40 accumulating data suggest an association in some Latino and Asian populations; although data are not entirely consistent. 19,22,41,42 Latinos who have varying European, African, and Native American ancestral composition share certain haplotypes with Asians, 43 in whom NQO1 associations with warfarin were documented. Our U.S. cohort included Latinos from the UAZ, who are presumably of mostly Mexican descent, as suggested by the genetic ancestry analysis, and UIC, who we previously reported were of predominantly Mexican descent, 19 with mostly European and Native American ancestry.…”

Section: Genetic Warfarin Determinants In Latinosmentioning

confidence: 99%

Multi‐site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos

Rouby

Marcatto

Claudio

et al. 2020

Clinical Translational Sci

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We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.-1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (β = −0.29, P < 2.0 × 10 −16 ; β = −0.21, P = 4.7 × 10 −7 , respectively) whereas CYP4F2 and NQO1 variants were associated with higher dose (β = 0.10, P = 2 × 10 −4 ; β = 0.10, P = 0.01, respectively). Associations with VKORC1 (β = −0.14, P = 2.0 × 10 −16), CYP2C9 (β = −0.07, P = 5.6 × 10 −10), and CYP4F2 (β = 0.03, P = 3 × 10 −3), but not NQO1*2 (β = 0.01, P = 0.30), were replicated in the Brazilians, explaining 43-46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants in VKORC1, CYP2C9, and CYP4F2 with warfarin dose in Latinos from the United States and Brazil. Although the use of direct acting oral anticoagulants is increasing, warfarin remains commonly prescribed for prevention and treatment of thromboembolic events. 1,2 Complicating therapy with warfarin is the drug's narrow therapeutic index and high interpatient variability in dose requirements. 3 Latinos are at notably high risk for poor outcomes as a result of nontherapeutic anticoagulation with warfarin. 4-8 Particularly alarming is the increased risk for warfarin-related intracranial hemorrhage in Latinos compared with non-Latino whites. 7 Latinos also have a higher recurrence rate of thrombotic events and worse outcomes from these events compared with whites. 5,

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“…Studies in Caucasians and African-Americans show that CYP2C9 , [5] VKORC1 , [6–8] CYP4F2 , [9] EPHX1 , [10] CALU , [11] APOE , [12,13] and PROC [14] polymorphisms can significantly affect interindividual variability of warfarin dosing. In addition, several studies in Asian populations have found that polymorphisms in GGCX , [15,16] NQO1 , [17] and HNF4α [18] are also associated with warfarin dosing, indicating that gene polymorphisms affecting warfarin dose requirements vary among different racial groups. The genetic makeup of the Chinese population differs from that of other ethnic groups; therefore, novel gene loci influencing warfarin dosing were found in Chinese patients.…”

Section: Introductionmentioning

confidence: 99%

Clinical and genetic factors associated with warfarin maintenance dose in northern Chinese patients with mechanical heart valve replacement

Cao

Zhang

et al. 2017

Medicine

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The effects of genetic variants on warfarin dosing vary among different ethnic groups, especially in the Chinese population. The objective of this study was to recruit patients through a rigorous experimental design and to perform a comprehensive screen to identify gene polymorphisms that may influence warfarin dosing in northern Han Chinese patients with mechanical heart valve replacement. Consenting patients (n = 183) with a stable warfarin dose were included in this study. Ninety-six single nucleotide polymorphisms (SNPs) in 30 genes involved in warfarin pharmacological pathways were genotyped using the Illumina SNP GoldenGate Assay, and their associations with warfarin dosing were assessed using univariate regression analysis with post hoc comparison using least significant difference analysis. Multiple linear regression was performed by incorporating patients' clinical and genetic data to create a new algorithm for warfarin dosing. From the 96 SNPs analyzed, VKORC1 rs9923231, CYP1A2 rs2069514, CYP3A4 rs28371759, and APOE rs7412 were associated with higher average warfarin maintenance doses, whereas CYP2C9 rs1057910, EPHX1 rs2260863, and CYP4F2 rs2189784 were associated with lower warfarin doses (P < 0.05). Multiple linear regression analysis could estimate 44.4% of warfarin dose variability consisting of, in decreasing order, VKORC1 rs9923231 (14.2%), CYP2C9 * 3 (9.6%), body surface area (6.7%), CYP1A2 rs2069514 (3.7%), age (2.7%), CYP3A4 rs28371759 (2.5%), CYP4F2 rs2108622 (1.9%), APOE rs7412 (1.7%), and VKORC1 rs2884737 (1.4%). In the dosing algorithm we developed, we confirmed the strongest effects of VKORC1, CYP2C9 on warfarin dosing. In the limited sample set, we also found that novel genetic predictors (CYP1A2, CYP3A4, APOE, EPHX1, CYP4F2, and VKORC1 rs2884737) may be associated with warfarin dosing. Further validation is needed to assess our results in larger independent northern Chinese samples.Abbreviations: ANOVA = one-way analysis of variance, BMI = body mass index, BSA = body surface area, INR = international normalized ratio, IWPC = International Warfarin Pharmacogenetics Consortium, MHVR = mechanical heart valve replacement, SNP = single nucleotide polymorphism.

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Effects of NAD(P)H quinone oxidoreductase 1 polymorphisms on stable warfarin doses in Korean patients with mechanical cardiac valves

Abstract: Our results demonstrate that NQO1 gene polymorphisms influence stable warfarin doses in Korean patients.

Cited by 14 publications

References 26 publications

Association of Nuclear Factor‐Erythroid 2‐Related Factor 2, Thioredoxin Interacting Protein, and Heme Oxygenase‐1 Gene Polymorphisms with Diabetes and Obesity in Mexican Patients

Association of Nuclear Factor‐Erythroid 2‐Related Factor 2, Thioredoxin Interacting Protein, and Heme Oxygenase‐1 Gene Polymorphisms with Diabetes and Obesity in Mexican Patients

Multi‐site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos

Clinical and genetic factors associated with warfarin maintenance dose in northern Chinese patients with mechanical heart valve replacement

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