title: Impact of VKORC1 gene polymorphisms on warfarin maintenance dosage: A novel systematic review and meta-analysis of 53 studies.
abstract: OBJECTIVE
  To analyze the correlation betweenVKORC1gene polymorphisms and warfarin maintenance dosage, as well as the correlation of dosage of warfarin with age and ethnicity.
  
  
  METHODS
  We retrieved related studies published between January 2000 and March 2016 from PubMed, Embase, the Cochrane Library, Web of Science, VIP, CNKI, and Wan Fang data. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data and crosscheck data. Then, RevMan5.3 software was used to perform a meta-analysis.
  
  
  RESULTS
  53 studies were included in the meta-analysis. The most prevalent genotypes were -1639 AA, 1173 TT, and 3730 GG in both Asian and Caucasians, but the distribution frequencies of all three were higher in Asians than in Caucasians. The meta-analysis showed that compared with homozygousVKORC1-1639 AA carriers, carriers of type GA, GG, and G (GA + GG) required 45% (95% confidence interval (CI) 42 - 49), 77% (95% CI 70 - 84), and 51% (95% CI 47 - 55) higher warfarin doses, respectively. Carriers of type CC, TC, and C (CC + TC) required 83% (95% CI 73 - 92), 26% (95% CI 23 - 29), and 53% (95% CI 44 - 62) higher warfarin doses, respectively, compared to homozygousVKORC11173 TT carriers. Carriers of type AA, GA, and A (AA + GA) required 40% (95% CI 29 - 51), 25% (95% CI 17 - 33), and 33% (95% CI 21 - 45) higher warfarin doses, respectively, compared to carriers of the homozygousVKORC13730 GG polymorphism (all p < 0.05). Subgroup analysis showed that Asian patients aged ≤ 60 years carrying 1173 CC, TC, and C genotypes required 28%, 39%, and 22% higher warfarin doses, respectively, compared with patients aged > 60 years. Caucasian patients aged > 60 years carrying -1639 GA, GG and G genotypes needed 24%, 39%, and 37% lower warfarin doses, respectively, compared with patients aged ≤ 60 years. These differences were statistically significant (p < 0.05).
  
  
  CONCLUSIONS
  Our study showed that the relationship between <italic>VKORC1</italic> gene polymorphisms and warfarin maintenance dose differs between individuals, and that individuals with different ages and ethnicities require different doses of warfarin. Caucasians carriers of genotype -1639 GG, G and 1173 CC, TC, C required a higher mean daily warfarin doses compared with Asian patients. Therefore, in order to achieve optimal treatment and lowest risk,VKORC1gene polymorphism detection is suggested. .
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Qing-Ping
authors.initials: QP
authors.lastname: Shi
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Yu
authors.forename: Jian
authors.initials: J
authors.lastname: Hua
authors.forename: Yong-Xin
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000367:Age Factors; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D054796:Drug Dosage Calculations; D005006:Ethnicity; D005787:Gene Frequency; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D064887:Observational Studies as Topic; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D011110:Polymorphism, Genetic; D064417:Vitamin K Epoxide Reductases / Q000235:genetics* / Q000378:metabolism; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases