影响心房颤动抗凝控制质量和血管事件的遗传与非遗传因素
Genetic and Non-Genetic Factors Affecting the Quality of Anticoagulation Control and Vascular Events in Atrial Fibrillation.
作者信息
Park Yun Kyung, Lee Mi Ji, Kim Jae Ha, Lee Jin Soo, Park Rae Woong, Kim Gyeong-Moon, Chung Chin-Sang, Lee Kwang Ho, Kim June Soo, Lee Soo-Youn, Bang Oh Young
机构信息
Department of Neurology, Konyang University School of Medicine, Daejeon, Republic of Korea.
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
出版信息
J Stroke Cerebrovasc Dis. 2017 Jun;26(6):1383-1390. doi: 10.1016/j.jstrokecerebrovasdis.2017.02.022. Epub 2017 Apr 12.
BACKGROUND
Warfarin has a narrow therapeutic window. We hypothesized that genetic factors related to warfarin metabolism (CYP2C9) and activity (VKORC1) would show stronger associations than modifiable factors with the quality of anticoagulation control and risks for thromboembolism and hemorrhage.
METHODS
In this retrospective cohort analysis, clinical and genetic data were collected from 380 patients with atrial fibrillation (AF) who were followed for an average observation period of 4 years. We evaluated the factors associated with time in therapeutic range (TTR, international normalized ratio [INR]: 2-3) and vascular events (either thromboembolic or hemorrhagic), including both genetic (CYP2C9 and VKORC1 genotype) and modifiable factors (anticoagulation service and warfarin dose assessment interval).
RESULTS
The genotypic frequency of CYP2C9*3 (rs1057910) was 9.5% and that of VKORC1 1173C>T (rs9934438) was 16.3%. TTR showed dependence on VKORC1 polymorphism: TTR was higher in carriers of the VKORC1 1173C>T than of the VKORC1 TT genotype (61.7 ± 16.0% versus 56.7 ± 17.4%, P = .031). Multivariate testing showed that the VKORC1 genotype and anticoagulation service were independently related to labile INRs (TTR <65%). Vascular events were observed in 66 patients (18.4%) during the study period. A Cox proportional hazard model showed that the use of anticoagulation service and patients' characteristics, such as AF-thromboembolic risk (CHADS-VASc score: Congestive heart failure, Hypertension, Age 75 years or older, Diabetes mellitus, previous Stroke or transient ischemic attack, Vascular disease, Age 65 to 74 years, female) and consequence (neurologic disability), but not genetic factors, were independently associated with vascular events.
CONCLUSIONS
Both genetic factor (VKORC1 genotype) and clinical efforts (anticoagulation service) influenced the quality of anticoagulation control. However, clinical events were more strongly associated with patient characteristics and clinical efforts than with genetic factors.
背景
华法林的治疗窗较窄。我们推测，与华法林代谢（CYP2C9）和活性（VKORC1）相关的遗传因素，相较于可改变因素，与抗凝控制质量以及血栓栓塞和出血风险的关联更强。
方法
在这项回顾性队列分析中，收集了380例房颤（AF）患者的临床和遗传数据，平均观察期为4年。我们评估了与治疗范围内时间（TTR，国际标准化比值[INR]：2 - 3）和血管事件（血栓栓塞或出血）相关的因素，包括遗传因素（CYP2C9和VKORC1基因型）和可改变因素（抗凝服务和华法林剂量评估间隔）。
结果
CYP2C9*3（rs1057910）的基因型频率为9.5%，VKORC1 1173C>T（rs9934438）的基因型频率为16.3%。TTR显示出对华法林VKORC1基因多态性的依赖性：VKORC1 1173C>T携带者的TTR高于VKORC1 TT基因型携带者（61.7±16.0%对56.7±17.4%，P = 0.031）。多变量检验表明，VKORC1基因型和抗凝服务与不稳定的INR（TTR <65%）独立相关。在研究期间，66例患者（18.4%）发生了血管事件。Cox比例风险模型显示，抗凝服务的使用以及患者特征，如房颤 - 血栓栓塞风险（CHADS - VASc评分：充血性心力衰竭、高血压、年龄75岁及以上、糖尿病、既往中风或短暂性脑缺血发作、血管疾病、年龄65至74岁、女性）和后果（神经功能障碍），而非遗传因素，与血管事件独立相关。
结论
遗传因素（VKORC1基因型）和临床措施（抗凝服务）均影响抗凝控制质量。然而，临床事件与患者特征和临床措施的关联比与遗传因素的关联更强。
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