Clinical and genetic factors associated with warfarin maintenance dose in northern Chinese patients with mechanical heart valve replacement.
Clinical and genetic factors associated with warfarin maintenance dose in northern Chinese patients with mechanical heart valve replacement.
复制标题
中国北方机械心脏瓣膜置换术患者华法林维持剂量相关的临床和遗传因素。
DOI：
10.1097/md.0000000000005658
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发表时间：
2017-01
期刊：
影响因子：
1.6
通讯作者：
Dong R
中科院分区：
文献类型：
--
作者：
Liu R;Cao J;Zhang Q;Shi XM;Pan XD;Dong R
补充数字内容可在文本中获得遗传变异对华法林剂量的影响在不同种族群体中存在差异，特别是在中国人群中。本研究的目的是通过严格的实验设计招募患者，并进行全面筛查，以确定可能影响北方汉族机械心脏瓣膜置换术患者华法林剂量的基因多态性。本研究纳入了华法林剂量稳定的患者（n =183）。 使用Illumina SNP GoldenGate Assay对参与华法林药理学途径的30个基因中的96个单核苷酸多态性（SNP）进行基因分型，并使用单变量回归分析评估其与华法林剂量的相关性，并使用最小显著差异分析进行事后比较。通过合并患者的临床和遗传数据进行多元线性回归，以创建华法林剂量的新算法。在分析的96个SNP中，VKORC1 rs9923231、CYP1A2 rs2069514、CYP3A4 rs28371759和APOE rs7412与较高的平均华法林维持剂量相关，而CYP2C9 rs1057910、EPHX 1 rs2260863和CYP4F2 rs2189784与较低的华法林剂量相关（P <0.05）。 多元线性回归分析可估计44.4%的华法林剂量变异性，包括（按降序排列）VKORC 1 rs9923231（14.2%），CYP2C9 ≥ 3（9.6%），体表面积（6.7%）、CYP1A2 rs2069514（3.7%）、年龄（2.7%）、CYP3A4 rs28371759（2.5%）、CYP4F2 rs2108622（1.9%）、APOE rs7412（1.7%）和VKORC 1 rs2884737（1.4%）。在我们开发的给药算法中，我们证实了VKORC 1、CYP2C9对华法林给药的最强影响。在有限的样本集中，我们还发现新的遗传预测因子（CYP1A2、CYP3A4、APOE、EPHX 1、CYP4F2和VKORC 1 rs2884737）可能与华法林给药相关。需要进一步验证，以评估我们的结果在更大的独立北方中国样本。
Supplemental Digital Content is available in the text The effects of genetic variants on warfarin dosing vary among different ethnic groups, especially in the Chinese population. The objective of this study was to recruit patients through a rigorous experimental design and to perform a comprehensive screen to identify gene polymorphisms that may influence warfarin dosing in northern Han Chinese patients with mechanical heart valve replacement. Consenting patients (n = 183) with a stable warfarin dose were included in this study. Ninety-six single nucleotide polymorphisms (SNPs) in 30 genes involved in warfarin pharmacological pathways were genotyped using the Illumina SNP GoldenGate Assay, and their associations with warfarin dosing were assessed using univariate regression analysis with post hoc comparison using least significant difference analysis. Multiple linear regression was performed by incorporating patients’ clinical and genetic data to create a new algorithm for warfarin dosing. From the 96 SNPs analyzed, VKORC1 rs9923231, CYP1A2 rs2069514, CYP3A4 rs28371759, and APOE rs7412 were associated with higher average warfarin maintenance doses, whereas CYP2C9 rs1057910, EPHX1 rs2260863, and CYP4F2 rs2189784 were associated with lower warfarin doses (P < 0.05). Multiple linear regression analysis could estimate 44.4% of warfarin dose variability consisting of, in decreasing order, VKORC1 rs9923231 (14.2%), CYP2C9∗3 (9.6%), body surface area (6.7%), CYP1A2 rs2069514 (3.7%), age (2.7%), CYP3A4 rs28371759 (2.5%), CYP4F2 rs2108622 (1.9%), APOE rs7412 (1.7%), and VKORC1 rs2884737 (1.4%). In the dosing algorithm we developed, we confirmed the strongest effects of VKORC1, CYP2C9 on warfarin dosing. In the limited sample set, we also found that novel genetic predictors (CYP1A2, CYP3A4, APOE, EPHX1, CYP4F2, and VKORC1 rs2884737) may be associated with warfarin dosing. Further validation is needed to assess our results in larger independent northern Chinese samples.