Genetic variation in the beta2 subunit of the voltage-gated calcium channel and pharmacogenetic association with adverse cardiovascular outcomes in the INternational VErapamil SR-Trandolapril STudy GENEtic Substudy (INVEST-GENES).
在国际维拉帕米 SR-Trandolapril 研究遗传亚研究 (INVEST-GENES) 中,电压门控钙通道 β 2 亚基的遗传变异和药物遗传学与不良心血管结果的关联。

摘要

BACKGROUND:Single-nucleotide polymorphisms (SNPs) within the regulatory β2 subunit of the voltage-gated calcium channel (CACNB2) may contribute to variable treatment response to antihypertensive drugs and adverse cardiovascular outcomes.
METHODS AND RESULTS:SNPs in CACNB2 from 60 ethnically diverse individuals were identified and characterized. Three common SNPs (rs2357928, rs7069292, and rs61839258) and a genome-wide association study-identified intronic SNP (rs11014166) were genotyped for a clinical association study in 5598 hypertensive patients with coronary artery disease randomized to a β-blocker (BB) or a calcium channel blocker (CCB) treatment strategy in the INternational VErapamil SR-Trandolapril STudy GENEtic Substudy (INVEST-GENES). Reporter gene assays were conducted on the promoter SNP, showing association with clinical outcomes. Twenty-one novel SNPs were identified. A promoter A>G SNP (rs2357928) was found to have significant interaction with treatment strategy for adverse cardiovascular outcomes (P for interaction, 0.002). In whites, rs2357928 GG patients randomized to CCB were more likely to experience an adverse outcome than those randomized to BB treatment strategy, with adjusted hazard ratio (HR) (CCB versus BB) of 2.35 (95% CI, 1.19 to 4.66; P=0.014). There was no evidence for such treatment difference in AG (HR, 1.16; 95% CI, 0.75 to 1.79; P=0.69) and AA (HR, 0.63; 95% CI, 0.36 to 1.11; P=0.11) patients. This finding was consistent in Hispanics and blacks. CACNB2 rs11014166 showed similar pharmacogenetic effect in Hispanics, but not in whites or blacks. Reporter assay analysis of rs2357928 showed a significant increase in promoter activity for the G allele compared to the A allele.
CONCLUSIONS:These data suggest that genetic variation within CACNB2 may influence treatment-related outcomes in high-risk patients with hypertension.

译文

背景: 电压门控钙通道 (CACNB2) 的调节 β 2 亚基内的单核苷酸多态性 (SNPs) 可能导致对抗高血压药物的不同治疗反应和不良心血管结果。
方法和结果: 对来自 60 个不同种族个体的 CACNB2 SNPs 进行了鉴定和表征。三个常见的 SNPs (rs2357928 、 rs7069292 和 rs61839258) 和一个全基因组关联研究确定的内含子 SNP (rs11014166) 对 5598 名患有冠状动脉疾病的高血压患者进行了临床关联研究,随机分配到 β 受体阻滞剂 (BB) 或钙通道阻滞剂 (CCB)国际维拉帕米 SR-Trandolapril 研究遗传亚研究 (INVEST-GENES) 中的治疗策略。对启动子 SNP 进行报告基因检测,显示与临床结果的关联。确定了 21 个新的 SNPs。发现启动子 A> G SNP (rs2357928) 与不良心血管结果的治疗策略有显著的相互作用 (相互作用 P,0.002)。在白人中,rs2357928 GG 随机分配到 CCB 的患者比那些随机分配到 BB 治疗策略的患者更有可能经历不良结局,调整后的风险比 (HR) (CCB vs BB) 2.35 (95% CI,1.19 至 4.66; P = 0.014)。在 AG (HR,1.16; 95% CI,0.75 到 1.79; P = 0.69) 和 AA (HR,0.63; 95% CI,0.36 到 1.11) 中没有这种处理差异的证据; P = 0.11) 患者。这一发现在西班牙裔和黑人中是一致的。CACNB2 rs11014166 在西班牙裔中显示出相似的药理作用,但在白人或黑人中没有。Rs2357928 的报告试验分析显示,与 a 等位基因相比,G 等位基因的启动子活性显著增加。
结论: 这些数据表明 CACNB2 内的遗传变异可能会影响高血压高危患者的治疗相关结果。

verapamil

心血管 钙离子通道阻滞剂 药物
概述  :  

维拉帕米,又名异搏定、戊脉安、凡拉帕米,系钙拮抗剂中的苯烷基胺类受体拮抗剂。作用机制为抑制窦房结和房室交界区的4相自动除极化,对窦房结自律性、窦房和房室传导性均有选择性抑制作用;它能抑制钙离子内流,影响兴奋收缩偶联,使心肌产生负性肌力和血管平滑肌松弛作用,因此,本药对心脏有负性频率、负性传导及使心肌收缩减低,血管扩张血压下降。毒理维拉帕米为钙离子通道阻滞剂,口服30~45分钟血中药物浓度达峰值,120分钟起效,高峰作用时间3~4小时,血清药效浓度为80~300 mg/L,半衰期3~7小时,主

Verapamil [və'ræpə,mɪl] 

释义   n. 戊脉安;异搏定(一种冠状动脉扩张药)

例句   To study the pharmacokinetics and pharmacodynamics of verapamil in patients with hypertension. 

研究维拉帕米在高血压患者的药代动力学及药效学。


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