Robust association of the LPA locus with low-density lipoprotein cholesterol lowering response to statin treatment in a meta-analysis of 30 467 individuals from both randomized control trials and observational studies and association with coronary artery disease outcome during statin treatment
Robust association of the LPA locus with low-density lipoprotein cholesterol lowering response to statin treatment in a meta-analysis of 30 467 individuals from both randomized control trials and observational studies and association with coronary artery disease outcome during statin treatment
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DOI：
10.1097/fpc.0b013e3283642fd6
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发表时间：
2013-10-01
影响因子：
2.6
通讯作者：
Palmer, Colin N. A.
中科院分区：
文献类型：
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作者：
Donnelly, Louise A.;van Zuydam, Natalie R.;Palmer, Colin N. A.
目的LPA单核苷酸多态性rs 10455872与他汀类药物降低低密度脂蛋白胆固醇（LDLc）的反应相关，是一种已知的冠状动脉疾病（CAD）标志物。然而，目前还不清楚什么样的CAD残留风险，这标志物可能在他汀类药物treatment.MethodsUsing电子病历链接到GoDARTS基因型人群，我们确定了超过8000例患者在泰赛德，Scotland.ResultsWe复制的RCT的结果，其中rs 10455872的G等位基因与响应他汀类药物治疗的LDL c每等位基因0.10 mmol/l较差降低相关，并对既往发表的随机对照试验进行荟萃分析（P=1.46x10（-29），n= 30467）。我们发现rs 10455872与他汀类药物治疗个体的CAD之间存在相关性，并在乌得勒支心血管药物遗传学研究中重复了这一发现（合并比值比1.41，95%置信区间1.17-1.68，P=4.5x10（-5），n=8822），表明他汀类药物治疗并不能消除这种明确的CAD遗传风险。此外，在一个考克斯比例风险模型与LDLc测量的时间依赖性，我们证明了CAD和rs 10455872之间的关系是独立的LDLc在他汀类药物treatment.ConclusionIndividuals与G等位基因的rs 10455872，这代表了约七分之一的患者，有一个更高的风险CAD比大多数的人口，即使治疗后与他汀类药物;因此代表了需要除他汀类药物治疗之外的替代药物的脆弱群体。
ObjectivesThe LPA single-nucleotide polymorphism rs10455872 has been associated with low-density lipoprotein cholesterol (LDLc) lowering response to statins in several randomized control trials (RCTs) and is a known coronary artery disease (CAD) marker. However, it is unclear what residual risk of CAD this marker may have during statin treatment.MethodsUsing electronic medical records linked to the GoDARTS genotyped population, we identified over 8000 patients on statins in Tayside, Scotland.ResultsWe replicated the findings of the RCTs, with the G allele of rs10455872 being associated with a 0.10 mmol/l per allele poorer reduction in LDLc in response to statin treatment, and conducted a meta-analysis with previously published RCTs (P=1.46x10(-29), n=30 467). We showed an association between rs10455872 and CAD in statin-treated individuals and have replicated this finding in the Utrecht Cardiovascular Pharmacogenetics study (combined odds ratio 1.41, 95% confidence interval 1.17-1.68, P=4.5x10(-5), n=8822) suggesting that statin treatment does not abrogate this well-established genetic risk for CAD. Furthermore, in a Cox proportional hazards model with LDLc measured time dependently, we demonstrated that the relationship between CAD and rs10455872 was independent of LDLc during statin treatment.ConclusionIndividuals with the G allele of rs10455872, which represents approximately one in seven patients, have a higher risk of CAD than the majority of the population even after treatment with statins; and therefore represent a vulnerable group requiring an alternative medication in addition to statin treatment.