New Loss-of-Function Mutations in PCSK9 Reduce Plasma LDL Cholesterol

作者：Fanhua Meng, Shuai Liu, Jian Xiao, Yüxia Zhou, Le-Wei Dong, Yunfeng Li, Yanqing Zhang, Weihui Li, Ju-Qiong Wang, Yan Wang, Bao‐Liang Song, Yi-Tong Ma, Zhen-Yan Fu, Jie Luo · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2023 · DOI：10.1161/atvbaha.122.318839 · 被引用次数：24 · 研究领域：Lipoproteins and Cardiovascular Health、Nuclear Structure and Function、Cholesterol and Lipid Metabolism

Background: Lower plasma levels of LDL (low-density lipoprotein) cholesterol (LDL-C) can reduce the risk of atherosclerotic cardiovascular disease. The loss-of-function mutations in PCSK9 (proprotein convertase subtilisin/kexin type 9) have been known to associate with low LDL-C in many human populations. PCSK9 genetic variants in Chinese Uyghurs who are at high risk of atherosclerotic cardiovascular disease due to their dietary habits have not been reported. Methods: The study involved the whole-exome and target sequencing of college students from Uyghur and other ethnic groups in Xinjiang, China, for the association of PCSK9 loss-of-function mutations with low plasma levels of LDL-C. The mechanisms by which the identified mutations affect the function of PCSK9 were investigated in cultured cells using biochemical and cell assays. The causal effects of the identified PCSK9 mutations on LDL-C levels were verified in mice injected with adeno-associated virus expressing different forms of PCSK9 and fed a high-cholesterol diet. Results: We identified 2 PCSK9 mutations—E144K and C378W—in Chinese Uyghurs with low plasma levels of LDL-C. The E144K and C378W mutations impaired the maturation and secretion of the PCSK9 protein, respectively. Adeno-associated virus–mediated expression of E144K and C378W mutants in Pcsk9 KO (knockout) mice fed a high-cholesterol diet also hampered PCSK9 secretion into the serum, resulting in elevated levels of LDL receptor in the liver and reduced leve...