Clinical Application of a Novel Genetic Risk Score for Ischemic Stroke in Patients With Cardiometabolic Disease.
Clinical Application of a Novel Genetic Risk Score for Ischemic Stroke in Patients With Cardiometabolic Disease.
复制标题
心脏代谢疾病患者中缺血性中风的新型遗传风险评分的临床应用。
DOI：
10.1161/circulationaha.120.051927
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发表时间：
2021-02-02
期刊：
影响因子：
37.8
通讯作者：
Ruff CT
中科院分区：
文献类型：
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作者：
Marston NA;Patel PN;Kamanu FK;Nordio F;Melloni GM;Roselli C;Gurmu Y;Weng LC;Bonaca MP;Giugliano RP;Scirica BM;O'Donoghue ML;Cannon CP;Anderson CD;Bhatt DL;Gabriel Steg P;Cohen M;Storey RF;Sever P;Keech AC;Raz I;Mosenzon O;Antman EM;Braunwald E;Ellinor PT;Lubitz SA;Sabatine MS;Ruff CT
全基因组关联研究已经确定了与中风风险增加相关的单核苷酸多态性（SNP）。我们试图确定遗传风险评分（GRS）是否可以在考虑了心脏代谢疾病谱的5项试验中的传统临床风险因素后识别出缺血性卒中风险较高的受试者。本分析纳入了ENGAGE AF-TIMI 48、SOLID-TIMI 52、SAVOR-TIMI 53、PEGASUS-TIMI 54和FOURIER试验中同意进行基因检测的欧洲血统受试者。使用一组与缺血性卒中相关的32个SNP来计算每个患者的GRS，并确定遗传风险的三分位数。采用考克斯模型计算遗传风险组间缺血性卒中的风险比，并校正临床风险因素。在5项试验的51，288例受试者中，共有960例受试者在中位随访期2.5年内发生缺血性卒中。在调整临床风险因素后，遗传风险增加与缺血性卒中风险增加密切相关（p趋势=0.009）。当与遗传风险最低的三分之一个体相比时，遗传风险中位和最高三分之一个体的缺血性卒中校正风险比分别为1.15（95%CI 0.98-1.36）和1.24（95%CI 1.05-1.45）。亚组分层显示，一级预防队列中GRS的表现似乎更强，最高与最低三分位数的校正HR为1.27（95% CI 1.04-1.53），而既往卒中受试者的校正HR为1.06（95% CI 0.81-1.41）。在对患有房颤且CHA 2DS 2-VASc为2的患者进行的探索性分析中，高遗传风险导致卒中风险增加4倍，绝对风险相当于CHA 2DS 2-VASc为3的患者。在广泛的心脏代谢疾病受试者中，32-SNP GRS是缺血性卒中的强有力的独立预测因子。在患有房颤但CHA 2DS 2-VASc评分较低的患者中，GRS确定的患者风险与CHA 2DS 2-VASc评分较高的患者相当。
Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in five trials across the spectrum of cardiometabolic disease. Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48, SOLID-TIMI 52, SAVOR-TIMI 53, PEGASUS-TIMI 54, and FOURIER trials were included in this analysis. A set of 32 SNPs associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors. In 51,288 subjects across the five trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, increasing genetic risk was strongly and independently associated with increased risk for ischemic stroke (p-trend=0.009). When compared to individuals in the lowest third of genetic risk, individuals in the middle and top tertiles of genetic risk had adjusted hazard ratios of 1.15 (95% CI 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted HR for the top versus lowest tertile of 1.27 (95% CI 1.04-1.53), compared with an adjusted HR of 1.06 (95% CI 0.81-1.41) in subjects with prior stroke. In an exploratory analysis of patients with atrial fibrillation and CHA2DS2-VASc of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA2DS2-VASc of 3. Across a broad spectrum of subjects with cardiometabolic disease, a 32-SNP GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA2DS2-VASc scores, the GRS identified patients with risk comparable to those with higher CHA2DS2-VASc scores.