Girelli Domenico, Piubelli Chiara, Martinelli Nicola, Corrocher Roberto, Olivieri Oliviero
Department of Medicine, Section of Internal Medicine, University of Verona, Italy.
Department of Medicine, Section of Internal Medicine, University of Verona, Italy.
Eur J Intern Med. 2017 Jun;41:10-17. doi: 10.1016/j.ejim.2017.03.019. Epub 2017 Apr 8.
Clinicians are well aware of the importance of a positive family history for coronary artery disease (CAD). Nonetheless, elucidation of the genetic basis of CAD has long proven difficult. The scenario changed in the last decade through the application of modern genomic technologies, like genome-wide association studies (GWAS) and next generation sequencing (NGS). GWAS have discovered over 60 common variants highly associated with CAD. For predictive purposes, such variants have been used to build up Genetic Risk Scores (GRSs), but their incorporation into classical prediction models does not appear substantially outperform the simple addition of family history. To date, the only strong case for the utility of incorporating genetic testing into clinical practice is represented by the diagnosis of Familial Hypercholesterolemia (FH). On the other hand, utilization of genomic techniques has driven formidable advances into the knowledge of CAD pathophysiology, particularly by addressing controversies on the causality of some lipid fractions that had long remained unsolved because of limitations of observational epidemiology. For example, NGS-derived rare variants with strong functional effects on key-genes like ANGPTL4, APOA5, APOC3, LPL, and SCARB1, have proven useful as proxies to demonstrate the causality of triglyceride-rich lipoproteins (TRLs) at variance with HDL-cholesterol concentration, thus contributing to tear down a dogma from classical epidemiology. Moreover, such variants have paved the way for the development of new biologic drugs (i.e. monoclonal antibodies or antisense oligonucleotides) targeting key proteins like PCSK9, Lipoprotein, and apolipoprotein C3. Such drugs are currently under active investigation, with first results being extremely promising.
临床医生深知冠心病（CAD）家族史呈阳性的重要性。尽管如此，长期以来，阐明CAD的遗传基础一直颇具难度。在过去十年中，随着现代基因组技术的应用，如全基因组关联研究（GWAS）和下一代测序（NGS），情况发生了变化。GWAS已经发现了60多个与CAD高度相关的常见变异。出于预测目的，这些变异已被用于构建遗传风险评分（GRS），但将它们纳入经典预测模型似乎并没有显著优于单纯添加家族史。迄今为止，将基因检测纳入临床实践的唯一有力案例是家族性高胆固醇血症（FH）的诊断。另一方面，基因组技术的应用推动了对CAD病理生理学认识的巨大进步，特别是通过解决一些长期以来因观察性流行病学的局限性而未得到解决的脂质组分因果关系争议。例如，通过NGS获得的对关键基因如血管生成素样蛋白4（ANGPTL4）、载脂蛋白A5（APOA5）、载脂蛋白C3（APOC3）、脂蛋白脂肪酶（LPL）和清道夫受体B1（SCARB1）具有强大功能影响的罕见变异，已被证明可作为代理来证明富含甘油三酯的脂蛋白（TRL）与高密度脂蛋白胆固醇浓度不同的因果关系，从而有助于打破经典流行病学的一个教条。此外，这些变异为开发针对关键蛋白如前蛋白转化酶枯草溶菌素9（PCSK9）、脂蛋白和载脂蛋白C3的新型生物药物（即单克隆抗体或反义寡核苷酸）铺平了道路。此类药物目前正在积极研究中，初步结果非常有前景。
