A spectrum of PCSK9 Alleles contributes to plasma levels of low-density lipoprotein cholesterol
A spectrum of PCSK9 Alleles contributes to plasma levels of low-density lipoprotein cholesterol
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DOI：
10.1086/500615
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发表时间：
2006-03-01
影响因子：
9.8
通讯作者：
Hobbs, HH
中科院分区：
文献类型：
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作者：
Kotowski, IK;Pertsemlidis, A;Hobbs, HH
前蛋白转化酶枯草杆菌蛋白酶/kexin 9型丝氨酸蛋白酶基因（PCSK 9）中的选择性错义突变导致常染色体显性高胆固醇血症，而同一基因中的无义突变与低血浆水平的低密度脂蛋白胆固醇（LDL-C）相关。在此，使用DNA测序和基于芯片的寡核苷酸杂交来确定PCSK 9中的其他序列变异是否有助于LDLC水平的差异。对来自达拉斯心脏研究（n= 3，543）的具有最低（<第5百分位数）和最高（>第195百分位数）LDL-C血浆水平的黑人和白人中的PCSK 9编码区进行测序。在鉴定的17种错义变体中，3种（R46 L、L253 F和A443 T）与LDL-C血浆水平降低（降低范围为3.5%-30%）显著且可重复相关。通过质子磁共振波谱测定，低LDL-C变异体均与肝脏甘油三酯含量增加无关。这一发现与主要由加速LDL清除而不是减少脂蛋白产生引起的LDL-C降低最为一致。对PCSK 9基因座上93个非编码单核苷酸多态性（SNP）进行的关联研究发现，3个SNP与血浆LDL-C水平的适度差异相关。因此，频率（0.2%-34%）和效应幅度（从增加3%到降低49%）范围内的序列变异谱导致了LDL-C水平的个体间差异。这些发现表明，PCSK 9活性是人体LDL-C血浆水平的主要决定因素，使其成为降低LDL-C的有吸引力的治疗靶点。
Selected missense mutations in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) cause autosomal dominant hypercholesterolemia, whereas nonsense mutations in the same gene are associated with low plasma levels of low-density lipoprotein cholesterol (LDL-C). Here, DNA sequencing and chip-based oligonucleotide hybridization were used to determine whether other sequence variations in PCSK9 contribute to differences in LDLC levels. The coding regions of PCSK9 were sequenced in the blacks and whites from the Dallas Heart Study (n=3,543) who had the lowest (< 5th percentile) and highest (> 195th percentile) plasma levels of LDL-C. Of the 17 missense variants identified, 3 (R46L, L253F, and A443T) were significantly and reproducibly associated with lower plasma levels of LDL-C (reductions ranging from 3.5% to 30%). None of the low-LDL-C variants were associated with increased hepatic triglyceride content, as measured by proton magnetic resonance spectroscopy. This finding is most consistent with the reduction in LDL-C being caused primarily by accelerating LDL clearance, rather than by reduced lipoprotein production. Association studies with 93 noncoding single-nucleotide polymorphisms (SNPs) at the PCSK9 locus identified 3 SNPs associated with modest differences in plasma LDL-C levels. Thus, a spectrum of sequence variations ranging in frequency (from 0.2% to 34%) and magnitude of effect (from a 3% increase to a 49% decrease) contribute to interindividual differences in LDL-C levels. These findings reveal that PCSK9 activity is a major determinant of plasma levels of LDL-C in humans and make it an attractive therapeutic target for LDL-C lowering.