본문 바로가기
KERD
논문KCI 등재

VKORC1 and CYP2C9 Genotype Variations in Relation to Warfarin Dosing in Korean StrokePatients

2

조회

0

다운로드

1

인용

0

참고문헌

키워드

주제분류신경과학

초록

Background and Purpose Variant alleles of CYP2C9 and VKORC1 account for differences in anticoagulation response. We sought to establish a warfarin dosing formula for individualized target International Normalization Ratio of Prothrombin Times (INRs) using data from single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 in Korean patients. Methods Ischemic stroke patients displaying stable target INR for at least 3 months before enrollment were analyzed. Warfarin and vitamin K levels were measured to adjust for confounders. Phenotypes were defined using the ’warfarin response index’ (WRI) defined as INR divided by the daily maintenance warfarin dose. We tested SNPs in CYP2C9 (3 sites: 430C>T (rs1799853), 1075A>C (rs1057910), 1076T>C) and VKORC1 (14 sites: 381C>T, 861C>A (rs17880887), 2653G>C, 3673A>G, 5496G>T, 5808T>G (r17882154), 6009C>T, 6484T>C (rs9934438), 6853C>T (rs17886369), 7566T>C, 8767G>C, 8814T>C, 9041G>A (rs17880624),and 9071G>T) using a standard sequencing method. Multivariate linear regression analysis was applied to establish the formula for warfarin dosage. Results All 204 patients had excellent drug compliance. The mean INR was 2.22 (+0.56)and mean daily maintenance dose of warfarin was 3.92 mg (+1.54). Patients with low WRI were younger (P<0.001) with high body mass index (P=0.003), high prevalence of wildtype CYP2C9 polymorphism (1075A>C, P<0.001), and six heterozygote SNPs in VRORC1(P<0.001), which were tightly interlinked (381T>C, 3673G>A, 6484T>C, 6853C>G. 7566C>T, 9041G>A) (r2=1). Based on these data, a warfarin dosing formula was established. Conclusions WRI is influenced by age, body mass index and SNPs in VKORC1 and CYP2C9in Korean stroke patients. The obtained warfarin dosing formula may be clinically applicable.

Abstract

Background and Purpose Variant alleles of CYP2C9 and VKORC1 account for differences in anticoagulation response. We sought to establish a warfarin dosing formula for individualized target International Normalization Ratio of Prothrombin Times (INRs) using data from single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 in Korean patients. Methods Ischemic stroke patients displaying stable target INR for at least 3 months before enrollment were analyzed. Warfarin and vitamin K levels were measured to adjust for confounders. Phenotypes were defined using the ’warfarin response index’ (WRI) defined as INR divided by the daily maintenance warfarin dose. We tested SNPs in CYP2C9 (3 sites: 430C>T (rs1799853), 1075A>C (rs1057910), 1076T>C) and VKORC1 (14 sites: 381C>T, 861C>A (rs17880887), 2653G>C, 3673A>G, 5496G>T, 5808T>G (r17882154), 6009C>T, 6484T>C (rs9934438), 6853C>T (rs17886369), 7566T>C, 8767G>C, 8814T>C, 9041G>A (rs17880624),and 9071G>T) using a standard sequencing method. Multivariate linear regression analysis was applied to establish the formula for warfarin dosage. Results All 204 patients had excellent drug compliance. The mean INR was 2.22 (+0.56)and mean daily maintenance dose of warfarin was 3.92 mg (+1.54). Patients with low WRI were younger (P<0.001) with high body mass index (P=0.003), high prevalence of wildtype CYP2C9 polymorphism (1075A>C, P<0.001), and six heterozygote SNPs in VRORC1(P<0.001), which were tightly interlinked (381T>C, 3673G>A, 6484T>C, 6853C>G. 7566C>T, 9041G>A) (r2=1). Based on these data, a warfarin dosing formula was established. Conclusions WRI is influenced by age, body mass index and SNPs in VKORC1 and CYP2C9in Korean stroke patients. The obtained warfarin dosing formula may be clinically applicable.

참고문헌 (46)

  1. Connolly S, "Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events: A randomised controlled trial", Lancet, 367, pp.1903~1912 (2006)
  2. Mihas C, "Warfarin versus aspirin for stroke prevention", Lancet, 370, pp.1606~ (2007)
  3. Harder S, "Clinically important drug interactions with anticoagulants. An update", Clin Pharmacokinet, 30, pp.416~444 (1996)
  4. Russmann S, "Age-dependent differences in the anticoagulant effect of phenprocoumon in patients after heart valve surgery", Eur J Clin Pharmacol, 52, pp.31~35 (1997)
  5. van Haeften TW, "Concordance of phenprocoumon dosage in married couples", BMJ, 314, pp.1386~ (1997)
  6. Sebastian JL, "Use of oral anticoagulants in older patients", Drugs Aging, 16, pp.409~435 (2000)
  7. Ufer M, "Identification of cytochromes p450 2C9 and 3A4 as the major catalysts of phenprocoumon hydroxylation in vitro", Eur J Clin Pharmacol, 60, pp.173~182 (2004)
  8. Heaf J, "Algorithm for short-term prescription of phenprocoumon", Haemostasis, 20, pp.21~30 (1990)
  9. Becquemont L, "Pharmacogenetics and interindividual variability in drug response: Cytochrome p-450 2C9 and coumarin anticoagulants", Bull Acad Natl Med, 190, pp.37~49 (2006)
  10. Engen RM, "Ethnic differences in pharmacogenetically relevant genes", Curr Drug Targets, 7, pp.1641~1648 (2006)
  11. Voora D, "The pharmacogenetics of coumarin therapy", Pharmacogenomics, 6, pp.503~513 (2005)
  12. Yoshizawa M, "Effect of VKORC1-1639 G>A; a polymorphism, body weight, age, and serum albumin alterations on warfarin response in japanese patients", Thromb Res, 124, pp.161~166 (2009)
  13. D’Andrea G, "A polymorphism in the VKORC1 gene is associated with an interindividual variability in the doseanticoagulant effect of warfarin", Blood, 105, pp.645~649 (2005)
  14. Klein TE, "Estimation of the warfarin dose with clinical and pharmacogenetic data", N Engl J Med, 360, pp.753~764 (2009)
  15. Hirsh J, "Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range", Chest, 119, pp.8~21 (2001)
  16. Rettie AE, "The pharmocogenomics of warfarin: Closing in on personalized medicine", Mol Interv, 6, pp.223~227 (2006)
  17. Sconce EA, "Appraisal of current vitamin k dosing algorithms for the reversal of over-anticoagulation with warfarin: The need for a more tailored dosing regimen", Eur J Haematol, 77, pp.457~462 (2006)
  18. Lal S, "Pharmacogenetics of target genes across the warfarin pharmacological pathway", Clin Pharmacokinet, 45, pp.1189~1200 (2006)
  19. Daly AK, "Pharmacogenetics of oral anticoagulants", Pharmacogenetics, 13, pp.247~252 (2003)
  20. Wu AH, "Use of genetic and nongenetic factors in warfarin dosing algorithms", Pharmacogenomics, 8, pp.851~861 (2007)
  21. Vladutiu GD, "The FDA announces new drug labeling for pharmacogenetic testing: Is personalized medicine becoming a reality?", Mol Genet Metab, 93, pp.1~4 (2008)
  22. Wu AH, "Dosing algorithm for warfarin using CYP2C9 and VKOTC1 genotyping from a multi-ethnic population: Comparison with other equations", Pharmacogenomics, 9, pp.169~178 (2008)
  23. Mushiroda T, "Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in japanese patients", J Hum Genet, 51, pp.249~253 (2006)
  24. Kimura R, "Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome p450 2C9 as determinants of daily warfarin dose in japanese patients", Thromb Res, 120, pp.181~186 (2007)
  25. Yoshizawa M, "Effect of VKORC1-1639 G>A polymorphism, body weight, age, and serum albumin alterations on warfarin response in japanese patients", Thromb Res, 124, pp.161~166 (2009)
  26. Cha PC, "High-resolution snp and haplotype maps of the human gamma-glutamyl carboxylase gene (GGCX) and association study between polymorphisms in ggcx and the warfarin maintenance dose requirement of the japanese population", J Hum Genet, 52, pp.856~864 (2007)
  27. Wen MS, "Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes", Clin Pharmacol Ther, 84, pp.83~89 (2008)
  28. Huang SW, "Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: A prospective study in Chinese patients", Pharmacogenet Genomics, 19, pp.226~234 (2009)
  29. Kim HS, "Effect of CYP2C9 and VKORC1 genotypes on early-phase and steadystate warfarin dosing in korean patients with mechanical heart valve replacement", Pharmacogenet Genomics, 19, pp.103~112 (2009)
  30. Cho HJ, "Development and comparison of a warfarin-dosing algorithm for Korean patients with atrial fibrillation", Clin Ther, 33, pp.1371~1380 (2011)
  31. Cho HJ, "Factors affecting the interindividual variability of warfarin dose requirement in adult Korean patients", Pharmacogenomics, 8, pp.329~337 (2007)
  32. Salem DN, "Antithrombotic therapy in valvular heart disease-- native and prosthetic: The seventh ACCP conference on antithrombotic and thrombolytic therapy", Chest, 126, pp.457~482 (2004)
  33. Yoo SH, "Age- and weightadjusted warfarin initiation nomogram for ischaemic stroke patients", Eur J Neurol, 19, pp.1547~1553 (2012)
  34. Favaloro EJ, "Standardization of the inr: How good is your laboratory’s inr and can it be improved?", Semin Thromb Hemost, 34, pp.593~603 (2008)
  35. Kammerer B, "Determination of (r)- and (s)-phenprocoumon in human plasma by enantioselective liquid chromatography", electrospray ionisation tandem mass spectrometry, 2004, pp.18, 458~464
  36. Naidong W, "Development and validation of a sensitive and robust LC-tandem MS method for the analysis of warfarin enantiomers in human plasma", J Pharm Biomed Anal, 25, pp.219~226 (2001)
  37. Suhara Y, "Method for the determination of vitamin k homologues in human plasma using high-performance liquid chromatography-tandem mass spectrometry", Anal Chem, 77, pp.757~763 (2005)
  38. Rieder MJ, "Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose", N Engl J Med, 352, pp.2285~2293 (2005)
  39. Pearson ES, "Biometric tables for statisticians", pp.2~8 (1972), Cambridge University Presss
  40. van HTW, "Concordance of phenprocoumon dosage in married couples", BMJ, 314, pp.1386~ (1997)
  41. Gage BF, "Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin", Clin Pharmacol Ther, 84, pp.326~331 (2008)
  42. Wadelius M, "The largest prospective warfarin-treated cohort supports genetic forecasting", Blood, 113, pp.784~792 (2009)
  43. Cooper GM, "A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose", Blood, 112, pp.1022~1027 (2008)
  44. Sconce EA, "The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: Proposal for a new dosing regimen", Blood, 106, pp.2329~2333 (2005)
  45. Miao L, "Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: Proposal for a new dosing regimen in chinese patients", Eur J Clin Pharmacol, 63, pp.1135~1141 (2007)
  46. Zhu Y, "Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes", Clin Chem, 53, pp.1199~1205 (2007)

관련 논문AI추천

Development and Comparison of Warfarin Dosing Algorithms in Stroke Patients이경아, 이경열, 조선미, 최종락연세대학교의과대학 · Yonsei Medical Journal2016 · 제57권 제3호Development and Validation of a Novel Warfarin Dosing Algorithm for Korean Patients With VKORC1 1173C이수연, 조은혜, 최리화, Hyun-Jung Cho, Insuk Sohn, June Soo Kim, Kyunghoon Lee, Mina Yang, Oh Young Bang, Sun-Young Baek, Young Keun On대한진단검사의학회 · Annals of Laboratory Medicine2020 · 제40권 제3호뇌혈관질환의 항혈전제 치료에 있어서 약물유전학이경열대한뇌졸중학회 · 대한뇌졸중영문학회지2010 · 제12권 제3호Quality of Anticoagulation with Warfarin in Korean Patients with Atrial Fibrillation and Prior Stroke: A Multicenter Retrospective Observational Study이준, 권순억, 김동억, 김성은, 김양기, 나정호, 남효석, 박만석, 박종무, 박태환, 방오영, 배희준, 윤병우, 이경복, 이병철, 이준영, 이지성, 차재관, 최재철, 홍근식대한신경과학회 · Journal of Clinical Neurology2017 · 제13권 제3호Lack of Association of Clinical Factors (SAMe- TT2R2) with CYP2C9/VKORC1 Genotype and Anticoagulation Control Quality김준수, 박윤경, 방오영, 이미지, 이수연, Jae Ha Kim, Suk Jae Kim대한뇌졸중학회 · 대한뇌졸중영문학회지2015 · 제17권 제2호Determination of Plasma Warfarin Concentrations in Korean Patients and Its Potential for Clinical Application권민정, 김종원, 김준수, 김희진, 손기호, 온영근, 이경훈, 이수연, 조현정대한진단검사의학회 · Annals of Laboratory Medicine2009 · 제29권 제6호

이 간행물의 다른 논문 (7건)