华法林维持剂量及治疗范围内时间的遗传决定因素：RE-LY基因组学子研究
Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range: a RE-LY genomics substudy.
作者信息
Eriksson Niclas, Wallentin Lars, Berglund Lars, Axelsson Tomas, Connolly Stuart, Eikelboom John, Ezekowitz Michael, Oldgren Jonas, Paré Guillaume, Reilly Paul, Siegbahn Agneta, Syvanen Ann-Christine, Wadelius Claes, Yusuf Salim, Wadelius Mia
机构信息
Uppsala Clinical Research Center & Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Department Medical Sciences & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
出版信息
Pharmacogenomics. 2016 Aug;17(13):1425-39. doi: 10.2217/pgs-2016-0061. Epub 2016 Aug 4.
AIMS
We investigated associations between genetic variation in candidate genes and on a genome-wide scale with warfarin maintenance dose, time in therapeutic range (TTR), and risk of major bleeding.
MATERIALS & METHODS: In total, 982 warfarin-treated patients from the RE-LY trial were studied.
RESULTS
After adjusting for SNPs in VKORC1 and CYP2C9, SNPs in DDHD1 (rs17126068) and NEDD4 (rs2288344) were associated with dose. Adding these SNPs and CYP4F2 (rs2108622) to a base model increased R(2) by 2.9%. An SNP in ASPH (rs4379440) was associated with TTR (-6.8% per minor allele). VKORC1 was associated with time less than INR 2.0. VKORC1 and CYP2C9 were associated with time more than INR 3.0, but not with major bleeding.
CONCLUSIONS
We identified two novel genes associated with warfarin maintenance dose and one gene associated with TTR. These genes need to be replicated in an independent cohort.
目的
我们研究了候选基因的遗传变异与华法林维持剂量、治疗范围内时间（TTR）以及大出血风险之间在全基因组范围内的关联。
材料与方法
总共对来自RE-LY试验的982名接受华法林治疗的患者进行了研究。
结果
在对维生素K环氧化物还原酶复合体亚单位1（VKORC1）和细胞色素P450 2C9（CYP2C9）中的单核苷酸多态性（SNP）进行校正后，二氢神经酰胺去饱和酶结构域含蛋白1（DDHD1，rs17126068）和神经前体细胞表达发育下调蛋白4（NEDD4，rs2288344）中的SNP与剂量相关。将这些SNP以及细胞色素P450 4F2（CYP4F2，rs2108622）添加到基础模型中使决定系数（R²）提高了2.9%。天冬氨酸β-羟化酶（ASPH，rs4379440）中的一个SNP与TTR相关（每个次要等位基因降低6.8%）。VKORC1与国际标准化比值（INR）小于2.0的时间相关。VKORC1和CYP2C9与INR大于3.0的时间相关，但与大出血无关。
结论
我们鉴定出两个与华法林维持剂量相关的新基因以及一个与TTR相关的基因。这些基因需要在独立队列中进行重复验证。
Zotero 插件