Department of Epidemiology, University College London, London, UK.
Int J Epidemiol. 2011 Apr;40(2):470-8. doi: 10.1093/ije/dyq205. Epub 2010 Nov 14.
Lipoprotein(a) [Lp(a)] is an established risk factor for coronary disease and stroke, but mechanisms underlying this association are unknown. We examined the association of Lp(a) with early atherosclerosis by using conventional epidemiologic analysis and a Mendelian randomization analysis. The latter utilized genetic variants that are associated with Lp(a) to estimate causal effect.
A prospective population-based cohort study of 939 men and 1141 women was conducted. Lp(a) was measured repeatedly at mean ages 17 and 38 years. Measurements of carotid intima-media thickness (IMT) and brachial flow-mediated dilation (FMD) at mean ages 32 and 38 years were used to determine the level and 6-year progression of subclinical atherosclerosis. Lp(a)-related genetic variant, rs783147, was identified by a genome wide association analysis (P = 3.1 × 10⁻⁵⁸), and a genetic score was constructed based on 10 Lp(a)-related variants. Mendelian randomization test was performed using a two-stage instrumental variables analysis.
rs783147 and the genetic score were strong instruments for nonconfounded Lp(a) levels (F-statistics 269.6 and 446.0 in the first-stage instrumental variable analysis). However, Lp(a) levels were not associated with the levels of or change in IMT or FMD in any of the conventional and instrumental variables tests. The null finding was observed both with rs783147 and the genetic score as instruments and remained unchanged after adjustment for clinical characteristics, such as age, sex, HDL and LDL cholesterol, ApoB, systolic and diastolic blood pressure, diabetes and smoking.
Data from conventional and Mendelian randomization analyses provide no support for early atherogenic effects of increased Lp(a) levels.
脂蛋白(a)[Lp(a)]是冠心病和中风的既定风险因素，但这种关联的机制尚不清楚。我们通过常规流行病学分析和孟德尔随机化分析来研究 Lp(a)与早期动脉粥样硬化的关系。后者利用与 Lp(a)相关的遗传变异来估计因果效应。
对 939 名男性和 1141 名女性进行前瞻性人群队列研究。在平均年龄为 17 岁和 38 岁时多次测量 Lp(a)。在平均年龄为 32 岁和 38 岁时测量颈动脉内膜中层厚度(IMT)和肱动脉血流介导的扩张(FMD)，以确定亚临床动脉粥样硬化的水平和 6 年进展情况。通过全基因组关联分析(P=3.1×10⁻⁵⁸)确定与 Lp(a)相关的遗传变异 rs783147，并基于 10 个 Lp(a)相关变异构建遗传评分。使用两阶段工具变量分析进行孟德尔随机化检验。
rs783147 和遗传评分是用于非混杂 Lp(a)水平的强工具(F 统计量在第一阶段工具变量分析中分别为 269.6 和 446.0)。然而，在任何常规和工具变量检验中，Lp(a)水平与 IMT 或 FMD 的水平或变化均无关。无论使用 rs783147 还是遗传评分作为工具，均观察到零假设，并且在调整年龄、性别、高密度脂蛋白胆固醇和低密度脂蛋白胆固醇、载脂蛋白 B、收缩压和舒张压、糖尿病和吸烟等临床特征后，该结果保持不变。
常规和孟德尔随机化分析的数据均不支持 Lp(a)水平升高的早期促动脉粥样硬化作用。
