Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany.
LIFE Research Center for Civilization Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany.
Hum Mol Genet. 2022 Mar 21;31(6):999-1011. doi: 10.1093/hmg/ddab279.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in lipid metabolism, as it degrades low-density lipoprotein (LDL) receptors from hepatic cell membranes. So far, only variants of the PCSK9 gene locus were found to be associated with PCSK9 levels. Here we aimed to identify novel genetic loci that regulate PCSK9 levels and how they relate to other lipid traits. Additionally, we investigated to what extend the causal effect of PCSK9 on coronary artery disease (CAD) is mediated by low-density lipoprotein-cholesterol (LDL-C).
We performed a genome-wide association study meta-analysis of PCSK9 levels in up to 12 721 samples of European ancestry. The estimated heritability was 10.3%, which increased to 12.6% using only samples from patients without statin treatment. We successfully replicated the known PCSK9 hit consisting of three independent signals. Interestingly, in a study of 300 African Americans, we confirmed the locus with a different PCSK9 variant. Beyond PCSK9, our meta-analysis detected three novel loci with genome-wide significance. Co-localization analysis with cis-eQTLs and lipid traits revealed biologically plausible candidate genes at two of them: APOB and TM6SF2. In a bivariate Mendelian Randomization analysis, we detected a strong effect of PCSK9 on LDL-C, but not vice versa. LDL-C mediated 63% of the total causal effect of PCSK9 on CAD.
Our study identified novel genetic loci with plausible candidate genes affecting PCSK9 levels. Ethnic heterogeneity was observed at the PCSK9 locus itself. Although the causal effect of PCSK9 on CAD is mainly mediated by LDL-C, an independent direct effect also occurs.
前蛋白转化酶枯草溶菌素/ 分泌酶 9（PCSK9）是脂质代谢的关键因子，因为它可从肝细胞膜上降解低密度脂蛋白（LDL）受体。到目前为止，仅发现 PCSK9 基因座的变体与 PCSK9 水平相关。在这里，我们旨在鉴定新的遗传位点，以调节 PCSK9 水平，并研究它们与其他脂质特征的关系。此外，我们还研究了 PCSK9 对冠状动脉疾病（CAD）的因果效应在多大程度上是由低密度脂蛋白胆固醇（LDL-C）介导的。
我们对多达 12721 个欧洲血统样本进行了 PCSK9 水平的全基因组关联研究荟萃分析。估计的遗传率为 10.3%，而仅使用未经他汀类药物治疗的患者样本，遗传率增加到 12.6%。我们成功复制了由三个独立信号组成的已知 PCSK9 命中。有趣的是，在一项对 300 名非裔美国人的研究中，我们证实了具有不同 PCSK9 变体的基因座。除了 PCSK9 之外，我们的荟萃分析还检测到三个具有全基因组意义的新基因座。与 cis-eQTL 和脂质特征的共定位分析揭示了其中两个基因座的生物学上合理的候选基因：APOB 和 TM6SF2。在双变量孟德尔随机化分析中，我们检测到 PCSK9 对 LDL-C 的影响很强，但反之亦然。LDL-C 介导了 PCSK9 对 CAD 的总因果效应的 63%。
我们的研究确定了具有影响 PCSK9 水平的合理候选基因的新遗传位点。PCSK9 基因座本身存在种族异质性。尽管 PCSK9 对 CAD 的因果效应主要是通过 LDL-C 介导的，但也会发生独立的直接效应。
