Iatan Iulia, Dastani Zari, Do Ron, Weissglas-Volkov Daphna, Ruel Isabelle, Lee Jenny C, Huertas-Vazquez Adriana, Taskinen Marja-Riitta, Prat Annik, Seidah Nabil G, Pajukanta Päivi, Engert James C, Genest Jacques
Department of Biochemistry, Cardiovascular Research Laboratories, Cardiology Division, McGill University Health Centre/Royal Victoria Hospital, Montreal, Quebec, Canada.
Circ Cardiovasc Genet. 2009 Oct;2(5):467-75. doi: 10.1161/CIRCGENETICS.109.877811. Epub 2009 Aug 22.
A low level of plasma high-density lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular disease. HDL particles are modulated by a variety of lipases, including endothelial lipase, a phospholipase present on vascular endothelial cells. The proprotein convertase subtilisin/kexin type 5 (PCSK5) gene product is known to directly inactivate endothelial lipase and indirectly cleave and activate angiopoetin-like protein 3, a natural inhibitor of endothelial lipase. We therefore investigated the effect of human PCSK5 genetic variants on plasma HDL-C levels.
Haplotypes at the PCSK5 locus were examined in 9 multigenerational families that included 60 individuals with HDL-C <10th percentile. Segregation with low HDL-C in 1 family was found. Sequencing of the PCSK5 gene in 12 probands with HDL-C <5th percentile identified 7 novel variants. Using a 2-stage design, we first genotyped these single-nucleotide polymorphisms (SNPs) along with 163 tagSNPs and 12 additional SNPs (n=182 total) in 457 individuals with documented coronary artery disease. We identified 9 SNPs associated with HDL-C (P<0.05), with the strongest results for rs11144782 and rs11144766 (P=0.002 and P=0.005, respectively). The SNP rs11144782 was also associated with very low-density lipoprotein (P=0.039), triglycerides (P=0.049), and total apolipoprotein levels (P=0.022). In stage 2, we replicated the association of rs11144766 with HDL-C (P=0.014) in an independent sample of Finnish low HDL-C families. In a combined analysis of both stages (n=883), region-wide significance of rs11144766 and low HDL-C was observed (unadjusted P=1.86x10(-4) and Bonferroni-adjusted P=0.031).
We conclude that variability at the PCSK5 locus influences HDL-C levels, possibly through the inactivation of endothelial lipase activity, and, consequently, atherosclerotic cardiovascular disease risk.
血浆高密度脂蛋白胆固醇（HDL-C）水平较低是心血管疾病的一个危险因素。HDL颗粒受多种脂肪酶调节，包括血管内皮细胞上存在的一种磷脂酶——内皮脂肪酶。已知前蛋白转化酶枯草杆菌蛋白酶/kexin 5型（PCSK5）基因产物可直接使内皮脂肪酶失活，并间接切割和激活血管生成素样蛋白3，后者是内皮脂肪酶的天然抑制剂。因此，我们研究了人类PCSK5基因变异对血浆HDL-C水平的影响。
在9个多代家庭中检查了PCSK5基因座的单倍型，这些家庭包括60名HDL-C处于第10百分位数以下的个体。在1个家庭中发现与低HDL-C存在分离现象。对12名HDL-C处于第5百分位数以下的先证者的PCSK5基因进行测序，发现了7个新的变异。采用两阶段设计，我们首先在457名有冠状动脉疾病记录的个体中对这些单核苷酸多态性（SNP）以及163个标签SNP和另外12个SNP（共182个）进行基因分型。我们鉴定出9个与HDL-C相关的SNP（P<0.05），其中rs11144782和rs11144766的结果最强（分别为P=0.002和P=0.005）。SNP rs11144782还与极低密度脂蛋白（P=0.039）、甘油三酯（P=0.049）和总载脂蛋白水平（P=0.022）相关。在第二阶段，我们在芬兰低HDL-C家庭的独立样本中重复了rs11144766与HDL-C的关联（P=0.014）。在两个阶段的联合分析（n=883）中，观察到rs11144766与低HDL-C的全区域显著性（未校正P=1.86×10⁻⁴，Bonferroni校正P=0.031）。
我们得出结论，PCSK5基因座的变异性可能通过使内皮脂肪酶活性失活而影响HDL-C水平，进而影响动脉粥样硬化性心血管疾病风险。
