Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement--a systematic review and meta analysis.
BACKGROUND
Warfarin is the most widely used oral anticoagulant. It has been suggested that anticoagulation effect of warfarin is significantly associated with the polymorphism of certain genes, including Cytochrome P450 complex subunit 2C9 (CYP2C9), Vitamin K Epoxide Reductase Complex Subunit 1 (VKORC1), Gamma-Glutamyl Carboxylase (GGCX) and Apolipoprotein E (APOE) etc. The purpose of the present study was to conduct a systemic review and meta-analysis to investigate the relationship between mean daily warfarin dose (MDWD) and VKORC1 single nucleotide polymorphisms (SNPs).


METHODS
Inclusion and exclusion criteria were made, and the studies between 2004 and present were searched. References were examined, and experts were consulted for additional information. Data were extracted. Revman 4.2.10 software was applied to analyze the relationship between MDWD and VKORC1 SNPs.


RESULTS
Total 19 studies were included in the meta-analysis. The frequencies of 1173TT and -1639 AA in Asian patients were higher than those in Caucasian and African populations. Patients with VKORC1 1173 CT and 1173 CC required 44% [95% Confidence Interval (CI); 32%, 56%] and 97% [73%, 122%] higher MDWD than 1173 TT carriers, -1639GA and -1639GG carriers required 52% [41%, 64%] and 102% [85%, 118%] higher MDWD than -1639AA carriers, 3730GA and 3730AA carriers required 27% [3%, 58%] and 52% [3%, 109%] higher MDWD than 3730GG carriers. In addition, 1173C, -1639 G and 3730 A carriers required 63% [44%, 82%], 61% [49%, 73%] and 32% [4%, 59%] higher MDWD than 1173TT, -1639 AA and 3730GG, respectively. Sensitive analyses demonstrated that the impacts of gene polymorphism on warfarin dosage requirement were significantly different between Caucasian and Asian population, and the results of meta-analyses were stable and reliable.


CONCLUSIONS
This is the first meta-analysis about the impact of VKORC1 gene polymorphism on warfarin dose requirement. Our studies showed that gene polymorphisms of VKORC1 significantly associated with the variation of interindividual warfarin dose requirement variation, and the effects are different in ethnicities.
Yang
Limei
L
Pharmacy Department, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Ge
Weihong
W
Yu
Feng
F
Zhu
Huaijun
H
D000925:Anticoagulants / Q000008:administration & dosage* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D019735:Carbon-Carbon Ligases / Q000235:genetics*; D002985:Clinical Protocols; D065729:Cytochrome P-450 CYP2C9; D005006:Ethnicity / Q000235:genetics; D006801:Humans; D011110:Polymorphism, Genetic; D011506:Proteins / Q000008:administration & dosage / Q000235:genetics; D044469:Racial Groups / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage* / Q000627:therapeutic use
D000925:Anticoagulants; D011506:Proteins; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase