Ridker Paul M, MacFadyen Jean G, Glynn Robert J, Chasman Daniel I
Center for Cardiovascular Disease Prevention and the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA 02215, USA.
Circ Cardiovasc Genet. 2011 Jun;4(3):312-7. doi: 10.1161/CIRCGENETICS.110.959353. Epub 2011 Apr 14.
Hypothesis-generating data raise the possibility that carriers of the kinesin-like protein 6 (KIF6) 719 arginine (Arg) allele preferentially benefit from statin therapy, and, on this basis, a commercial assay for KIF6 has been developed.
In the recently completed JUPITER trial, men and women without prior cardiovascular disease or diabetes who had baseline low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥ 2 mg/L were randomly allocated to rosuvastatin 20 mg daily or to placebo and followed for first major vascular events (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, arterial revascularization, or vascular death) and for all-cause mortality. We evaluated the effect of polymorphism at rs20455 encoding the KIF6 719Arg allele on outcomes in this primary prevention trial, both among Caucasian participants and in the trial as a whole. Among 8781 Caucasian trial participants, we observed no increase in vascular event rates among carriers of the KIF6 719Arg allele as compared with noncarriers (hazard ratio, 0.91; 95% confidence interval, 0.66 to 1.26) nor any difference in percent low-density lipoprotein cholesterol reduction with rosuvastatin according to genotype (-52 versus -52 mg/dL, P = 0.11). Rosuvastatin allocation was associated with an almost identical reduction in the trial primary end point among carriers (hazard ratio, 0.61; 95% confidence interval, 0.43 to 0.87) as among noncarriers (hazard ratio, 0.59; 95% confidence interval, 0.39 to 0.88) (P-interaction = 0.90). Genotype had no impact on rosuvastatin efficacy in further analyses that included all-cause mortality, in analyses conducted in the total trial cohort that adjusted for race, or in analyses using generalized models of inheritance rather than recessive models.
In the large primary prevention JUPITER trial, rosuvastatin was equally effective at reducing cardiovascular event rates among carriers and noncarriers of the KIF6 719Arg allele. Thus, at least for rosuvastatin, there appears to be no clinical utility to screening for KIF6 genotype as a method to determine vascular risk or to predict statin efficacy. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.
产生假设的数据提示，携带驱动蛋白样蛋白6（KIF6）719精氨酸（Arg）等位基因的个体可能从他汀类药物治疗中获得更大益处，基于此，已开发出一种针对KIF6的商业检测方法。
在最近完成的JUPITER试验中，无心血管疾病或糖尿病病史、基线低密度脂蛋白胆固醇<130mg/dL且高敏C反应蛋白≥2mg/L的男性和女性被随机分配至每日服用瑞舒伐他汀20mg组或安慰剂组，并随访首次主要血管事件（非致死性心肌梗死、非致死性卒中、因不稳定型心绞痛住院、动脉血运重建或血管性死亡）及全因死亡率。我们在这项一级预防试验中评估了编码KIF6 719Arg等位基因的rs20455位点多态性对结局的影响，包括在白种人参与者中以及在整个试验人群中。在8781名白种人试验参与者中，我们观察到携带KIF6 719Arg等位基因者与非携带者相比，血管事件发生率并未增加（风险比，0.91；95%置信区间，0.66至1.26），且根据基因型，瑞舒伐他汀降低低密度脂蛋白胆固醇的百分比也无差异（-52对-52mg/dL，P=0.11）。瑞舒伐他汀治疗组中，携带KIF6 719Arg等位基因者与非携带者相比，试验主要终点事件的降低幅度几乎相同（风险比，0.61；95%置信区间，0.43至0.87）（风险比，0.59；95%置信区间，0.39至0.88）（P交互作用=0.90）。在纳入全因死亡率的进一步分析中、在对种族进行校正的整个试验队列分析中或使用遗传广义模型而非隐性模型的分析中，基因型对瑞舒伐他汀疗效均无影响。
在大型一级预防JUPITER试验中，瑞舒伐他汀在降低携带和不携带KIF6 719Arg等位基因者的心血管事件发生率方面同样有效。因此，至少对于瑞舒伐他汀而言，筛查KIF6基因型作为确定血管风险或预测他汀疗效的方法似乎并无临床实用性。临床试验注册-网址：http://www.clinicaltrials.gov。唯一标识符：NCT00239681。
