Circulation：基因多态性决定达比加群血药浓度及出血风险

RE-LY试验（Randomized Evaluation of Long-term Anticoagulation Therapy）结果显示达比加群酯110mg及150mg（每日两次）在预防非瓣膜性房颤患者卒中上优于华法林。两种剂型达比加群酯的大出血和轻微出血风险均较低。与维生素K拮抗剂不同，达比加群酯为固定剂量且不需抗凝监测。但达比加群活性代谢物血药浓度在不同个体之间存在较大的差异。遗传变异是否会导致达比加群活性代谢物血药浓度的个体差异进而影响其安全性和有效性？对此加拿大的研究人员Paré G等对达比加群酯代谢过程中的酯酶基因CES1 以及达比加群转运过程中的P糖蛋白外转运体 ABCA1 的常见遗传变异进行分析。其结果发表在2013年4月2日的Circulation杂志上。
研究人员对参与RE-LY试验的2944名受试者进行全基因组关联分析。研究的主要安全结局是任何原因的出血（包括大出血和轻微出血）。其中1490例有达比加群药物浓度数据。对达比加群峰谷浓度进行基因组关联分析发现CES1基因单核苷酸多态性（SNP）rs2244613 与达比加群谷浓度相关，ABCB1基因SNP rs4148738和CES1基因SNP rs8192935与峰值浓度相关。在受试者中，CES1基因SNP rs2244613的每一个次要等位基因与较低的谷浓度相关（每个等位基因降低15%），有较低的出血风险，也有减少大出血风险趋势但无统计学意义。华法林与达比加群的相互作用与携带状态明显相关，次要等位基因携带者服用达比加群治疗要比华法林治疗出血风险小，而对于非次要等位基因携带者两药出血风险无差别，其与缺血事件无关。SNP rs4148738 和rs8192935与出血或缺血事件均无关。
在RE-LY受试者中，全基因组关联分析发现携带有 CES1 rs2244613 次要等位基因的患者占32.8%，可降低达比加群活性代谢物的作用时间。携带该基因多态性则出血风险较低。
该研究提供了这样一种可能性即常规基因分型有助于临床进一步权衡达比加群剂量从而实现个体治疗，进而在药物安全性和有效性达到平衡。
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Genetic determinants of dabigatran plasma levels and their relation to bleeding.
BACKGROUND
Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in the prevention of stroke in atrial fibrillation patients compared with warfarin. We hypothesized that genetic variants could contribute to interindividual variability in blood concentrations of the active metabolite of dabigatran etexilate and influence the safety and efficacy of dabigatran.
METHODS AND RESULTS
We successfully conducted a genome-wide association study in 2944 Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) participants. The CES1 single-nucleotide polymorphism rs2244613 was associated with trough concentrations, and the ABCB1 single-nucleotide polymorphism rs4148738 and the CES1 single-nucleotide polymorphism rs8192935 were associated with peak concentrations at genome-wide significance (P<9×10(-8)) with a gene-dose effect. Each minor allele of the CES1 single-nucleotide polymorphism rs2244613 was associated with lower trough concentrations (15% decrease per allele; 95% confidence interval, 10-19; P=1.2×10(-8)) and a lower risk of any bleeding (odds ratio, 0.67; 95% confidence interval, 0.55-0.82; P=7×10(-5)) in dabigatran-treated participants, with a consistent but nonsignificant lower risk of major bleeding (odds ratio, 0.66; 95% confidence interval, 0.43-1.01). The interaction between treatment (warfarin versus all dabigatran) and carrier status was statistically significant (P=0.002), with carriers having less bleeding with dabigatran than warfarin (hazard ratio, 0.59; 95% confidence interval, 0.46-0.76; P=5.2×10(-)5) in contrast to no difference in noncarriers (hazard ratio, 0.96; 95% confidence interval, 0.81-1.14; P=0.65). There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events.
CONCLUSIONS
Genome-wide association analysis identified that carriage of the CES1 rs2244613 minor allele occurred in 32.8% of patients in RE-LY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding.