Association of apolipoprotein E (APOE) polymorphisms with warfarin maintenance dose in a northern Han Chinese population.
Association of apolipoprotein E (APOE) polymorphisms with warfarin maintenance dose in a northern Han Chinese population.
复制标题
中国北方汉族人群载脂蛋白 E (APOE) 多态性与华法林维持剂量的关联。
DOI：
10.1186/s12944-016-0205-8
复制
发表时间：
2016-02-24
影响因子：
4.5
通讯作者：
Dong R
中科院分区：
文献类型：
--
作者：
Liu R;Zhang K;Gong ZZ;Shi XM;Zhang Q;Pan XD;Dong R
载脂蛋白E（apoE）诱导肝脏摄取富含维生素K的脂蛋白，这可能影响华法林剂量需求的个体间差异。APOE基因多态性与华法林剂量之间的关系在不同种族人群中的报道并不一致，因此本研究在北方汉族机械心脏瓣膜患者中调查了这种关系。共纳入186例接受机械心脏瓣膜置换术并达到稳定华法林剂量的患者。使用Illumina SNP GoldenGate Assay对APOE单核苷酸多态性（SNP）rs7412和rs 429358进行基因分型。基因分型结果通过直接测序得到证实。使用PHASE v2.1软件构建rs7412和rs 429358单倍型。统计分析不同APOE基因型对华法林剂量的影响。华法林的平均维持剂量为3.10 ± 0.96 mg/天，平均国际标准化比值（INR）为2.09 ± 0.24。APOE E2、E3和E4等位基因频率分别为11.6%、82.5%和5.9%。未检测到E2/E2或E4/E4基因型。E2/E3、E3/E3、E2/E4和E3/E4基因型频率分别为21.0%、67.2%、2.2%和9.7%。在E2/E3、E3/E3和E3/E4基因型患者中观察到华法林剂量需求的显著差异（p < 0.05）。在事后比较中，与E3/E3纯合子相比，E2/E3杂合子的每日华法林维持剂量显著更高（p < 0.05），但E3/E4和E3/E3或E2/E3和E3/E4之间的剂量需求没有差异（p > 0.05）。将患者分为低强度抗凝治疗组（1.6 ≤ INR <2.0）和相对高强度抗凝治疗组（2.0 ≤ INR ≤2.5），两个亚组中E2/E3杂合子的华法林剂量需求均明显高于E3/E3纯合子（p < 0.05）。校正其他混杂因素后的多变量分析显示，E2/E3基因型与华法林剂量显著高于E3/E3基因型（p < 0.05）。中国北方汉族人群的APOE等位基因和基因型频率似乎与中国其他地区的其他种族群体或人群不同。APOE E2变异与华法林维持剂量显著升高相关。因此，APOE多态性可能是影响华法林剂量的预测因子之一。
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. 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. 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). 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.