Puccetti L, Bruni F, Pasqui A L, Pastorelli M, Ciani F, Palazzuoli A, Acampa M, Auteri A
Department of Clinical Medicine and Immunology, Internal Medicine Division, Centre for Atherosclerosis Research, University of Siena, Siena, Italy.
Eur J Clin Invest. 2008 Jan;38(1):11-6. doi: 10.1111/j.1365-2362.2007.01891.x.
Recent data indicate that statins could offer coronary artery disease (CAD) benefit even by mechanisms beyond lipid lowering. Genetic influence has been shown for some antithrombotic actions of statins via oxidized-low-density lipoprotein cholesterol (ox-LDL) receptors and nitric oxide synthase (NOS) activity modulation. The present study was designed to evaluate the influence of ox-LDL lectin-like receptor-1 (LOX-1) and NOS polymorphisms in the incidence of cardiovascular events in pure hypercholesterolaemic subjects during statin treatment.
A prospective 4-year study involving 1039 event-free subjects (643 males, 396 females) treated with atorvastatin (10-40 mg day(-1)) to reach the appropriate Adult Treatment Panel-III LDL target of 3.36 mmol L(-1). Enrolled subjects were evaluated every 6 months or at a clinical event. LOX-1 3'UTR/T-C and NOS G894T polymorphisms were detected by allelic discrimination assays (polymerase chain reaction), lipid profile by enzymatic-colorimetric method, ox-LDL by enzyme linked immunosorbent assay, platelet activation by P-selectin (P-sel) expression (FACScan), NOS activity (by intracellular citrullin recovery) and homocysteine (high performance liquid chromatography), C-reactive protein (CRP) by sensitive nephelometric technique.
LOX-1 3'UTR/T showed the strongest association with events in the whole cohort with respect to each other variable including LDL reduction and NOS G894T (OR 4.90, 95% CI 3.19-6.98, P < 0.00001). Smoking influenced events in LDL-targeted subjects (P < 0.0001). Ox-LDL and P-sel were better indicators than LDL or other variables according to 3'UTR/C genotype regardless of the magnitude of LDL reduction (OR 4.21, 95% CI 2.29-6.70 P < 0.0001).
LOX-1 polymorphisms could influence statin effectiveness in CAD prevention by induction of sensitivity to antithrombotic mechanisms such as antiplatelet activity.
近期数据表明，他汀类药物甚至可通过降脂以外的机制对冠状动脉疾病（CAD）产生有益作用。他汀类药物的某些抗血栓形成作用已显示出受遗传因素影响，其作用途径包括氧化型低密度脂蛋白胆固醇（ox-LDL）受体和一氧化氮合酶（NOS）活性的调节。本研究旨在评估ox-LDL凝集素样受体-1（LOX-1）和NOS基因多态性对单纯高胆固醇血症患者在他汀类药物治疗期间心血管事件发生率的影响。
一项为期4年的前瞻性研究，纳入1039例无心血管事件的受试者（男性643例，女性396例），给予阿托伐他汀（10 - 40 mg·day⁻¹）治疗，以达到成人治疗专家组III设定的合适低密度脂蛋白（LDL）目标值3.36 mmol·L⁻¹。每6个月或在发生临床事件时对纳入的受试者进行评估。通过等位基因鉴别分析（聚合酶链反应）检测LOX-1 3'UTR/T - C和NOS G894T基因多态性，采用酶比色法检测血脂谱，酶联免疫吸附测定法检测ox-LDL，通过P-选择素（P-sel）表达（流式细胞仪）检测血小板活化，通过细胞内瓜氨酸回收率检测NOS活性，采用高效液相色谱法检测同型半胱氨酸，采用敏感散射比浊技术检测C反应蛋白（CRP）。
在整个队列中，与包括LDL降低和NOS G894T在内的其他变量相比，LOX-1 3'UTR/T与事件的关联性最强（比值比4.90，95%可信区间3.19 - 6.98，P < 0.00001）。吸烟对以LDL为目标的受试者发生事件有影响（P < 0.0001）。无论LDL降低幅度如何，根据3'UTR/C基因型，ox-LDL和P-sel比LDL或其他变量是更好的指标（比值比4.21，95%可信区间2.29 - 6.70，P < 0.0001）。
LOX-1基因多态性可能通过诱导对抗血栓形成机制（如抗血小板活性）的敏感性来影响他汀类药物在CAD预防中的有效性。
