Common and Low-Frequency Genetic Variants in the PCSK9 Locus Influence Circulating PCSK9 Levels
Common and Low-Frequency Genetic Variants in the PCSK9 Locus Influence Circulating PCSK9 Levels
复制标题
DOI：
10.1161/atvbaha.111.240549
复制
发表时间：
2012-06-01
影响因子：
8.7
通讯作者：
van 't Hooft, Ferdinand M.
中科院分区：
文献类型：
--
作者：
Chernogubova, Ekaterina;Strawbridge, Rona;van 't Hooft, Ferdinand M.
目的：蛋白转化酶枯草素/可溶蛋白9 （PCSK9）是一种影响血浆低密度脂蛋白浓度和冠心病易感性的循环蛋白。循环PCSK9水平显示出相当大的个体间差异，但导致这种差异的因素在很大程度上是未知的。方法和结果：我们分析了4组健康中年瑞典人（n=5722）的循环PCSK9水平，发现PCSK9水平在大约50倍的范围内变化，与血浆低密度脂蛋白-胆固醇浓度呈正相关，与血浆甘油三酯、纤维蛋白原、胰岛素和葡萄糖浓度相关。在2个队列（n=1215）中进行的全基因组关联研究未能发现与循环PCSK9水平变化密切相关的常见遗传变异。正如预期的那样，PCSK9 R46L变异的次要等位基因在所有队列中都与PCSK9水平降低和血浆低密度脂蛋白-胆固醇浓度降低相关，但与血浆甘油三酯浓度没有关系。对PCSK9位点的进一步定位揭示了一个共同的多态性（rs2479415，次要等位基因频率43.9%），位于PCSK9上游约6 kb处，与循环PCSK9水平升高独立相关。结论：PCSK9位点的常见和低频遗传变异影响健康中年白人（主要是瑞典人）受试者循环PCSK9水平的显著个体间差异。（中华动脉血栓与血管杂志，2012;32:1526-1534）
Objective-Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that influences plasma low-density lipoprotein concentration and susceptibility to coronary heart disease. Circulating PCSK9 levels show considerable interindividual differences, but the factors responsible for this variation are largely unknown.Methods and Results-We analyzed circulating PCSK9 levels in 4 cohorts of healthy, middle-aged Swedes (n=5722) and found that PCSK9 levels varied over approximate to 50-fold range, showed a positive relationship with plasma low-density lipoprotein-cholesterol concentration, and were associated with plasma triglyceride, fibrinogen, insulin, and glucose concentrations. A genome-wide association study conducted in 2 cohorts (n=1215) failed to uncover common genetic variants robustly associated with variation in circulating PCSK9 level. As expected, the minor allele of the PCSK9 R46L variant was in all cohorts associated with reduced PCSK9 levels and decreased plasma low-density lipoprotein-cholesterol concentrations, but no relationship was observed with the plasma triglyceride concentration. Further mapping of the PCSK9 locus revealed a common polymorphism (rs2479415, minor allele frequency 43.9%), located approximate to 6 kb upstream from PCSK9, which is independently associated with increased circulating PCSK9 levels.Conclusion-Common and low-frequency genetic variants in the PCSK9 locus influence the pronounced interindividual variation in circulating PCSK9 levels in healthy, middle-aged white (predominantly Swedish) subjects. (Arterioscler Thromb Vasc Biol. 2012;32:1526-1534.)