Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada.
Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada; Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada.
J Clin Lipidol. 2021 Jan-Feb;15(1):79-87. doi: 10.1016/j.jacl.2020.11.006. Epub 2020 Nov 24.
Combined hyperlipidemia (CHL) is a common disorder defined by concurrently elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels. Despite decades of study, the genetic basis of CHL remains unclear.
To characterize the genetic profiles of patients with CHL and compare them to those in patients with isolated hypercholesterolemia and isolated hypertriglyceridemia (HTG).
DNA from 259, 379 and 124 patients with CHL, isolated hypercholesterolemia and isolated HTG, respectively, underwent targeted sequencing. We assessed: 1) rare variants disrupting canonical LDL-C or TG metabolism genes; and 2) two polygenic scores-for elevated LDL-C and TG-calculated using common trait-associated single-nucleotide polymorphisms (SNPs). Genetic profiles were compared against 1000 Genomes Project controls.
Both CHL and isolated HTG patients had significantly increased odds of a high polygenic score for TG: 2.50 (95% confidence interval [CI] 1.61-3.88; P < 0.001) and 3.72 (95% CI 2.24-6.19; P < 0.001), respectively. CHL patients had neither a significant accumulation of rare variants for LDL-C or TG, nor a high polygenic score for LDL-C. In contrast, patients with isolated hypercholesterolemia had a 3.03-fold increased odds (95% CI 2.22-4.13; P < 0.001) of carrying rare variants associated with familial hypercholesterolemia, while patients with isolated HTG had a 2.78-fold increased odds (95% CI 1.27-6.10; P = 0.0136) of carrying rare variants associated with severe HTG.
CHL is genetically similar to isolated HTG, a known polygenic trait. Both cohorts had a significant accumulation of common TG-raising variants. Elevated LDL-C levels in CHL are not associated with common or rare LDL-C-related genetic variants.
混合型高脂血症（CHL）是一种常见病症，其特征为低密度脂蛋白胆固醇（LDL-C）和甘油三酯（TG）水平同时升高。尽管经过了数十年的研究，CHL 的遗传基础仍不清楚。
描述 CHL 患者的遗传特征，并将其与单纯高胆固醇血症和单纯高甘油三酯血症（HTG）患者进行比较。
对分别患有 CHL、单纯高胆固醇血症和单纯 HTG 的 259、379 和 124 名患者的 DNA 进行靶向测序。我们评估了：1）破坏经典 LDL-C 或 TG 代谢基因的罕见变异；2）使用常见的与性状相关的单核苷酸多态性（SNP）计算出的升高 LDL-C 和 TG 的两个多基因评分。将遗传特征与 1000 基因组计划对照进行比较。
CHL 和单纯 HTG 患者的 TG 高多基因评分的几率显著增加：2.50（95%置信区间 [CI] 1.61-3.88；P<0.001）和 3.72（95% CI 2.24-6.19；P<0.001）。CHL 患者既没有 LDL-C 或 TG 的罕见变异的大量积累，也没有 LDL-C 的高多基因评分。相比之下，单纯高胆固醇血症患者携带与家族性高胆固醇血症相关的罕见变异的几率增加了 3.03 倍（95% CI 2.22-4.13；P<0.001），而单纯 HTG 患者携带与严重 HTG 相关的罕见变异的几率增加了 2.78 倍（95% CI 1.27-6.10；P=0.0136）。
CHL 在遗传上与单纯 HTG 相似，后者是一种已知的多基因性状。两个队列均有大量常见的升高 TG 的变异。CHL 中的 LDL-C 水平升高与常见或罕见的 LDL-C 相关遗传变异无关。
