Institute for Translational Medicine & Therapeutics and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Trends Cardiovasc Med. 2009 Aug;19(6):195-201. doi: 10.1016/j.tcm.2009.12.003.
Several high-profile failures of lipid-related therapeutics in clinical trials have led to intense interest in improved discovery and preclinical prioritization of potential targets. The careful study of patients with rare monogenic disorders has played a key role in establishing the causal role of cholesterol in atherosclerosis and highlighting viable drug targets. Systematic efforts to extend the association of common variants linked with lipid levels to coronary disease enable assessment of the vascular consequences of lifelong differences in lipids due to variation in specific molecules. This application of genetic epidemiology, termed Mendelian randomization, may prove useful in informing ongoing drug development efforts.
几项备受瞩目的脂质相关治疗药物在临床试验中的失败,导致人们强烈关注如何改进潜在靶点的发现和临床前优先级排序。对患有罕见单基因疾病的患者进行仔细研究,在确定胆固醇在动脉粥样硬化中的因果作用以及突出可行的药物靶点方面发挥了关键作用。系统地努力将与脂质水平相关的常见变异与冠心病联系起来,能够评估由于特定分子的差异导致脂质终生差异对血管的影响。这种遗传流行病学的应用,称为孟德尔随机化,可能有助于为正在进行的药物开发工作提供信息。