Beitelshees Amber L, Gong Yan, Wang Danxin, Schork Nicholas J, Cooper-Dehoff Rhonda M, Langaee Taimour Y, Shriver Mark D, Sadee Wolfgang, Knot Harm J, Pepine Carl J, Johnson Julie A
Department of Pharmacy Practice, University of Florida, College of Pharmacy, Gainesville, USA.
Pharmacogenet Genomics. 2007 Sep;17(9):719-29. doi: 10.1097/FPC.0b013e32810f2e3c.
We sought to determine whether polymorphisms in the large-conductance calcium and voltage-dependent potassium (BK) channel beta1 subunit gene, KCNMB1, are associated with blood pressure response to verapamil SR or adverse outcomes in the GENEtic substudy of the INternational VErapamil SR/trandolapril STudy (INVEST-GENES).
KCNMB1 is involved in calcium sensitivity and hypertension. The association between variability in KCNMB1 and calcium antagonist response, however, has not been assessed.
Genetic samples were collected from 5979 patients in INVEST. Blood pressure response to verapamil SR and time to achieve blood pressure control was assessed in relation to Glu65Lys and Val110Leu genotypes. The primary outcome (all cause mortality, nonfatal myocardial infarction or nonfatal stroke) was compared between genotype groups, and interaction with verapamil SR therapy was assessed.
Systolic blood pressure response to verapamil SR did not differ by KCNMB1 genotype. Lys65 variant carriers, however, achieved blood pressure control earlier than Glu65Glu individuals [1.47 (interquartile ratio 2.77) versus 2.83 (interquartile ratio 4.17) months, P=0.01] and were less likely to require multiple drugs at the time of blood pressure control (adjusted odds ratio 0.43, 95% confidence interval 0.19-0.95). Leu110 variant carriers had a reduced risk of primary outcome (hazard ratio 0.68, 95% confidence interval 0.47-0.998). Subgroup analysis revealed this finding to be more pronounced in verapamil SR-assigned patients (hazard ratio 0.587, 95% confidence interval 0.33-1.04) compared with atenolol-assigned patients (hazard ratio 0.946, 95% confidence interval 0.56-1.59). No difference was seen in the occurrence of the primary outcome compared by codon 65 genotype.
Our findings suggest that KCNMB1 genotype influences responsiveness to verapamil SR and risk of adverse cardiovascular outcomes.
我们试图确定大电导钙和电压依赖性钾（BK）通道β1亚基基因KCNMB1中的多态性是否与国际维拉帕米缓释片/群多普利研究（INVEST）基因亚研究中对维拉帕米缓释片的血压反应或不良结局相关。
KCNMB1参与钙敏感性和高血压。然而，KCNMB1变异性与钙拮抗剂反应之间的关联尚未得到评估。
从INVEST研究中的5979例患者收集基因样本。评估了与Glu65Lys和Val110Leu基因型相关的对维拉帕米缓释片的血压反应及实现血压控制的时间。比较了基因型组之间的主要结局（全因死亡率、非致命性心肌梗死或非致命性卒中），并评估了与维拉帕米缓释片治疗的相互作用。
对维拉帕米缓释片的收缩压反应在KCNMB1基因型之间无差异。然而，Lys65变异携带者比Glu65Glu个体更早实现血压控制[1.47（四分位数间距2.77）对2.83（四分位数间距4.17）个月，P = 0.01]，且在血压控制时需要多种药物的可能性较小（校正比值比0.43，95%置信区间0.19 - 0.95）。Leu110变异携带者发生主要结局的风险降低（风险比0.68，95%置信区间0.47 - 0.998）亚组分析显示，与阿替洛尔治疗组患者（风险比0.946，95%置信区间0.56 - 1.59）相比，这一发现在维拉帕米缓释片治疗组患者中更为明显（风险比0.587，95%置信区间0.33 - 1.04）。按密码子65基因型比较，主要结局的发生率未见差异。
我们的研究结果表明，KCNMB1基因型影响对维拉帕米缓释片的反应性及不良心血管结局的风险。
