Tada Hayato, Kawashiri Masa-Aki, Yamagishi Masakazu
Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
J Hum Genet. 2017 Apr;62(4):453-458. doi: 10.1038/jhg.2016.159. Epub 2017 Jan 5.
Dyslipidemias, especially hyper-low-density lipoprotein cholesterolemia and hypertriglyceridemia, are important causal risk factors for coronary artery disease. Comprehensive genotyping using the 'next-generation sequencing' technique has facilitated the investigation of Mendelian dyslipidemias, in addition to Mendelian randomization studies using common genetic variants associated with plasma lipids and coronary artery disease. The beneficial effects of low-density lipoprotein cholesterol-lowering therapies on coronary artery disease have been verified by many randomized controlled trials over the years, and subsequent genetic studies have supported these findings. More recently, Mendelian randomization studies have preceded randomized controlled trials. When the on-target/off-target effects of rare variants and common variants exhibit the same direction, novel drugs targeting molecules identified by investigations of rare Mendelian lipid disorders could be promising. Such a strategy could aid in the search for drug discovery seeds other than those for dyslipidemias.
血脂异常，尤其是低高密度脂蛋白胆固醇血症和高甘油三酯血症，是冠状动脉疾病的重要病因风险因素。除了使用与血脂和冠状动脉疾病相关的常见基因变异进行孟德尔随机化研究外，利用“下一代测序”技术进行的综合基因分型促进了孟德尔血脂异常的研究。多年来，许多随机对照试验已经证实了降低低密度脂蛋白胆固醇疗法对冠状动脉疾病的有益效果，随后的基因研究也支持了这些发现。最近，孟德尔随机化研究先于随机对照试验。当罕见变异和常见变异的靶向/脱靶效应呈现相同方向时，针对罕见孟德尔脂质疾病研究确定的分子的新型药物可能很有前景。这种策略有助于寻找除血脂异常药物之外的药物研发种子。
