title: Association of apolipoprotein E (APOE) polymorphisms with warfarin maintenance dose in a northern Han Chinese population.
abstract: BACKGROUND
  Apolipoprotein E (apoE) induces the uptake of vitamin K-rich lipoproteins by the liver, which likely affects inter-individual variation of warfarin dosing requirements. Associations between APOE polymorphisms and warfarin dosing were previously reported inconsistently among different ethnic groups, so the present study investigated this association in northern Han Chinese patients with mechanical heart valve prosthesis.
  
  
  METHODS
  A total of 186 patients who underwent mechanical heart valve replacement and attained a stable warfarin dose were included. APOE single nucleotide polymorphisms (SNPs) rs7412 and rs429358 were genotyped using Illumina SNP GoldenGate Assay. Genotyping results were confirmed by direct sequencing. PHASE v2.1 software was used to construct rs7412 and rs429358 haplotypes. The effects of different APOE genotypes on warfarin dose were analyzed statistically.
  
  
  RESULTS
  The mean warfarin maintenance dose was 3.10 ± 0.96 mg/day, and the mean international normalized ratio (INR) was 2.09 ± 0.24. APOE E2, E3, and E4 allele frequencies were 11.6 %, 82.5 %, and 5.9 %, respectively. No E2/E2 or E4/E4 genotypes were detected in this population. E2/E3, E3/E3, E2/E4, and E3/E4 genotype frequencies were 21.0 %, 67.2 %, 2.2 %, and 9.7 %, respectively. Significant differences in warfarin dose requirements were observed among patients with E2/E3, E3/E3, and E3/E4 genotypes (p < 0.05). In post hoc comparison, daily warfarin maintenance doses were significantly higher in E2/E3 heterozygotes compared with E3/E3 homozygotes (p < 0.05), but no differences in dose requirements were found between E3/E4 and E3/E3, or E2/E3 and E3/E4 (p > 0.05). Patients were divided into low-intensity anticoagulant treatment group (1.6 ≤ INR <2.0) and relatively high-intensity anticoagulant treatment group (2.0 ≤ INR ≤ 2.5), and significantly higher warfarin dose requirements were observed in E2/E3 heterozygotes compared with E3/E3 homozygotes in both subgroups (p < 0.05). Multivariable analysis adjusting for other confounders showed that E2/E3 genotype was associated with a significantly higher warfarin dose compared with E3/E3 genotype (p < 0.05).
  
  
  CONCLUSIONS
  APOE allele and genotype frequencies in the northern Han Chinese population appear to differ from other racial groups or populations living in other regions of China. The APOE E2 variant was associated with a significantly higher warfarin maintenance dose. Thus, APOE polymorphisms could be one of the predictors influencing warfarin doses in this population.
authors.affiliation: Cardiac Surgery, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Street, Chaoyang District, Beijing, 100029, China. liurui20141224@163.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Cardiac Surgery, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Street, Chaoyang District, Beijing, 100029, China. zhangkui@hotmail.com.
authors.forename: Kui
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Street, Chaoyang District, Beijing, 100029, China.
authors.forename: Zhi-zhong
authors.initials: ZZ
authors.lastname: Gong
authors.affiliation: Division of Cardiology, Department of pediatrics, Shandong Provincial Hospital Affiliated to Shandong University, Jingwuweiqi Street, Huaiyin District, Jinan, 250000, China. shixinmiao1224@163.com.
authors.forename: Xin-miao
authors.initials: XM
authors.lastname: Shi
authors.affiliation: Department of Epidemiology, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Street, Chaoyang District, Beijing, 100029, China. zhqian0819@163.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Experimental Center, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Street, Chaoyang District, Beijing, 100029, China. panxiaodongsun@vip.sina.com.
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Pan
authors.affiliation: Cardiac Surgery, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Street, Chaoyang District, Beijing, 100029, China. dongrandoctor@163.com.
authors.forename: Ran
authors.initials: R
authors.lastname: Dong
mesh_terms: D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000235:genetics*; D044466:Asian People; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013923:Thromboembolism / Q000188:drug therapy; D014859:Warfarin / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D001057:Apolipoproteins E; D014859:Warfarin