Thompson John F, Hyde Craig L, Wood Linda S, Paciga Sara A, Hinds David A, Cox David R, Hovingh G Kees, Kastelein John J P
Helicos BioSciences, Cambridge, MA, USA.
Circ Cardiovasc Genet. 2009 Apr;2(2):173-81. doi: 10.1161/CIRCGENETICS.108.818062. Epub 2009 Feb 12.
Statins are effective at lowering low-density lipoprotein cholesterol and reducing risk of cardiovascular disease, but variability in response is not well understood. To address this, 5745 individuals from the Treating to New Targets (TNT) trial were genotyped in a combination of a whole-genome and candidate gene approach to identify associations with response to atorvastatin treatment.
A total of 291 988 single-nucleotide polymorphisms (SNPs) from 1984 individuals were analyzed for association with statin response, followed by genotyping top hits in 3761 additional individuals. None was significant at the whole-genome level in either the initial or follow-up test sets for association with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglyceride response. In addition to the whole-genome platform, 23 candidate genes previously associated with statin response were analyzed in these 5745 individuals. Three SNPs in apoE were most highly associated with low-density lipoprotein cholesterol response, followed by 1 in PCSK9 with a similar effect size. At the candidate gene level, SNPs in HMGCR were also significant though the effect was less than with those in apoE and PCSK9. rs7412/apoE had the most significant association (P=6x10(-30)), and its high significance in the whole-genome study (P=4x10(-9)) confirmed the suitability of this population for detecting effects. Age and gender were found to influence low-density lipoprotein cholesterol response to a similar extent as the most pronounced genetic effects.
Among SNPs tested with an allele frequency of at least 5%, only SNPs in apoE are found to influence statin response significantly. Less frequent variants in PCSK9 and smaller effect sizes in SNPs in HMGCR were also revealed.
他汀类药物在降低低密度脂蛋白胆固醇和降低心血管疾病风险方面有效，但对其反应的变异性尚未完全了解。为解决这一问题，对来自“治疗达新目标”（TNT）试验的5745名个体采用全基因组和候选基因相结合的方法进行基因分型，以确定与阿托伐他汀治疗反应相关的因素。
对1984名个体的总共291988个单核苷酸多态性（SNP）进行分析，以确定与他汀类药物反应的关联，随后对另外3761名个体中的显著位点进行基因分型。在与低密度脂蛋白胆固醇、高密度脂蛋白胆固醇或甘油三酯反应相关的关联的初始或后续测试集中，没有一个在全基因组水平上具有显著性。除了全基因组平台外，还对这5745名个体中先前与他汀类药物反应相关的23个候选基因进行了分析。载脂蛋白E（apoE）中的三个SNP与低密度脂蛋白胆固醇反应的相关性最高，其次是前蛋白转化酶枯草溶菌素9（PCSK9）中的一个SNP，其效应大小相似。在候选基因水平上，3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）中的SNP也具有显著性，但其效应小于apoE和PCSK9中的SNP。rs7412/apoE的关联性最为显著（P = 6×10⁻³⁰），其在全基因组研究中的高显著性（P = 4×10⁻⁹）证实了该人群适用于检测效应。发现年龄和性别对低密度脂蛋白胆固醇反应的影响程度与最显著的基因效应相似。
在等位基因频率至少为5%的测试SNP中，仅发现apoE中的SNP对他汀类药物反应有显著影响。还发现了PCSK9中频率较低的变异以及HMGCR中SNP的较小效应大小。
