Wang Jian, Dron Jacqueline S, Ban Matthew R, Robinson John F, McIntyre Adam D, Alazzam Maher, Zhao Pei Jun, Dilliott Allison A, Cao Henian, Huff Murray W, Rhainds David, Low-Kam Cécile, Dubé Marie-Pierre, Lettre Guillaume, Tardif Jean-Claude, Hegele Robert A
From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2439-2445. doi: 10.1161/ATVBAHA.116.308027. Epub 2016 Oct 20.
Next-generation sequencing technology is transforming our understanding of heterozygous familial hypercholesterolemia, including revision of prevalence estimates and attribution of polygenic effects. Here, we examined the contributions of monogenic and polygenic factors in patients with severe hypercholesterolemia referred to a specialty clinic.
We applied targeted next-generation sequencing with custom annotation, coupled with evaluation of large-scale copy number variation and polygenic scores for raised low-density lipoprotein cholesterol in a cohort of 313 individuals with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol >5.0 mmol/L (>194 mg/dL). We found that (1) monogenic familial hypercholesterolemia-causing mutations detected by targeted next-generation sequencing were present in 47.3% of individuals; (2) the percentage of individuals with monogenic mutations increased to 53.7% when copy number variations were included; (3) the percentage further increased to 67.1% when individuals with extreme polygenic scores were included; and (4) the percentage of individuals with an identified genetic component increased from 57.0% to 92.0% as low-density lipoprotein cholesterol level increased from 5.0 to >8.0 mmol/L (194 to >310 mg/dL).
In a clinically ascertained sample with severe hypercholesterolemia, we found that most patients had a discrete genetic basis detected using a comprehensive screening approach that includes targeted next-generation sequencing, an assay for copy number variations, and polygenic trait scores.
新一代测序技术正在改变我们对杂合子家族性高胆固醇血症的理解，包括患病率估计的修订和多基因效应的归因。在此，我们研究了单基因和多基因因素在转诊至专科诊所的严重高胆固醇血症患者中的作用。
我们对313名严重高胆固醇血症患者（定义为低密度脂蛋白胆固醇>5.0 mmol/L[>194 mg/dL]）进行了靶向新一代测序及定制注释，并结合大规模拷贝数变异评估和低密度脂蛋白胆固醇升高的多基因评分。我们发现：（1）通过靶向新一代测序检测到的单基因家族性高胆固醇血症致病突变存在于47.3%的个体中；（2）当纳入拷贝数变异时，单基因突变个体的比例增至53.7%；（3）当纳入多基因评分极高的个体时，该比例进一步增至67.1%；（4）随着低密度脂蛋白胆固醇水平从5.0 mmol/L升至>8.0 mmol/L（194 mg/dL升至>310 mg/dL），具有已识别遗传成分的个体比例从57.0%增至92.0%。
在一个经临床确诊的严重高胆固醇血症样本中，我们发现大多数患者具有离散的遗传基础，这是通过包括靶向新一代测序、拷贝数变异检测和多基因性状评分的综合筛查方法检测到的。
