Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy
Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy
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DOI：
10.1161/01.atv.0000204337.81286.1c
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发表时间：
2006-05-01
影响因子：
8.7
通讯作者：
Leren, TP
中科院分区：
文献类型：
--
作者：
Berge, KE;Ose, L;Leren, TP
目的 - 前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 基因编码前蛋白转化酶，可导致细胞表面低密度脂蛋白受体 (LDLR) 降解。因此，破坏 PCSK9 正常功能的 PCSK9 基因突变可能导致 LDLR 数量增加和低胆固醇血症。此外，在携带 PCSK9 基因突变的受试者中，他汀类药物的降胆固醇作用可能会增强。 方法和结果 - 我们通过 DNA 测序筛选了 38 名不相关的低胆固醇血症受试者以及 25 名不相关的家族性高胆固醇血症 (FH) 杂合子，他们对他汀类药物治疗 PCSK9 基因 12 个外显子的突变反应特别好。 38 名低胆固醇血症受试者中有 6 名 (15.8%) 的 PCSK9 基因 3 个突变 R46L、G106R 或 R237W 中的 1 个为杂合子。在对他汀类药物治疗反应特别好的 25 名 FH 杂合子组中，3 名 (8.8%) 为 PCSK9 基因 R46L 或 N157K 突变杂合子。 441 名没有 LDLR 基因或载脂蛋白 B-100 基因突变的高胆固醇血症受试者中，没有一人拥有这 4 个突变中的任何一个。结论 - 4 个错义突变 R46L、G106R、N157K 和 R237W 与低胆固醇血症相关，并可能增加对他汀类药物治疗的反应。
Objective - The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene encodes a proprotein convertase that causes degradation of cell surface low-density lipoprotein receptors (LDLRs). Mutations in the PCSK9 gene that disrupt the normal function of PCSK9 could therefore result in increased number of LDLRs and hypocholesterolemia. Also, the cholesterol-lowering effect of statins could be increased in subjects carrying mutations in the PCSK9 gene.Methods and Results - We have screened 38 unrelated hypocholesterolemic subjects as well as 25 unrelated familial hypercholesterolemia (FH) heterozygotes who responded particularly well to statin therapy for mutations in the 12 exons of the PCSK9 gene by DNA sequencing. Six of the 38 (15.8%) hypocholesterolemic subjects were heterozygous for 1 of the 3 mutations R46L, G106R, or R237W in the PCSK9 gene. In the group of 25 FH heterozygotes who responded particularly well to statin therapy, 3 (8.8%) were heterozygous for mutations R46L or N157K in the PCSK9 gene. None of 441 hypercholesterolemic subjects without mutations in the LDLR gene or in the apolipoprotein B-100 gene possessed any of the 4 mutations.Conclusion - The 4 missense mutations R46L, G106R, N157K, and R237W are associated with hypocholesterolemia and possibly increased response to statin therapy.