国际维拉帕米缓释片-群多普利研究基因子研究（INVEST-GENES）中电压门控钙通道β2亚基的基因变异与不良心血管结局的药物遗传学关联。
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).
作者信息
Niu Yuxin, Gong Yan, Langaee Taimour Y, Davis Heather M, Elewa Hazem, Beitelshees Amber L, Moss James I, Cooper-Dehoff Rhonda M, Pepine Carl J, Johnson Julie A
机构信息
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
出版信息
Circ Cardiovasc Genet. 2010 Dec;3(6):548-55. doi: 10.1161/CIRCGENETICS.110.957654.
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.
背景
电压门控钙通道（CACNB2）调节性β2亚基内的单核苷酸多态性（SNP）可能导致抗高血压药物的治疗反应差异以及不良心血管结局。
方法与结果
对60名不同种族个体的CACNB2中的SNP进行了鉴定和特征分析。对三个常见SNP（rs2357928、rs7069292和rs61839258）以及一项全基因组关联研究确定的内含子SNP（rs11014166）进行基因分型，用于国际维拉帕米缓释片 - 群多普利研究基因亚组（INVEST - GENES）中5598例患有冠状动脉疾病的高血压患者的临床关联研究，这些患者被随机分配接受β受体阻滞剂（BB）或钙通道阻滞剂（CCB）治疗策略。对启动子SNP进行了报告基因检测，显示其与临床结局相关。鉴定出21个新的SNP。发现启动子A>G SNP（rs2357928）与不良心血管结局的治疗策略有显著相互作用（交互作用P值为0.002）。在白人中，随机接受CCB治疗的rs2357928 GG患者比接受BB治疗策略的患者更易出现不良结局，调整后的风险比（HR）（CCB与BB相比）为2.35（95% CI，1.19至4.66；P = 0.014）。在AG（HR，1.16；95% CI，0.75至1.79；P = 0.69）和AA（HR，0.63；95% CI，0.36至1.11；P = 0.11）患者中没有这种治疗差异的证据。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类似的药物遗传学效应，但在白人和黑人中未显示。对rs2357928的报告基因检测分析显示，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内的基因变异可能影响高危高血压患者的治疗相关结局。
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