Department of Biochemistry, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada; Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
J Clin Lipidol. 2021 Jan-Feb;15(1):88-96. doi: 10.1016/j.jacl.2020.11.007. Epub 2020 Nov 24.
Susceptibility to severe hypertriglyceridemia (HTG), defined as plasma triglyceride (TG) levels ≥10 mmol/L (880 mg/dL), is conferred by both heterozygous rare variants in five genes involved in TG metabolism and numerous common single-nucleotide polymorphisms (SNPs) associated with TG levels.
To date, these genetic susceptibility factors have been comprehensively assessed primarily in severe HTG patients of European ancestry. Here, we expand our analysis to HTG patients of East Asian and Hispanic ancestry.
The genomic DNA of 336, 63 and 199 severe HTG patients of European, East Asian and Hispanic ancestry, respectively, was evaluated using a targeted next-generation sequencing panel to screen for: 1) rare variants in LPL, APOA5, APOC2, GPIHBP1 and LMF1; 2) common, small-to-moderate effect SNPs, quantified using a polygenic score; and 3) common, large-effect polymorphisms, APOA5 p.G185C and p.S19W.
While the proportion of individuals with high polygenic scores was similar, frequency of rare variant carriers varied across ancestries. Compared with ancestry-matched controls, Hispanic patients were the most likely to have a rare variant (OR = 5.02; 95% CI 3.07-8.21; p < 0.001), while European patients were the least likely (OR = 2.56; 95% CI 1.58-4.13; p < 0.001). The APOA5 p.G185C polymorphism, exclusive to East Asians, was significantly enriched in patients compared with controls (OR = 10.1; 95% CI 5.6-18.3; p < 0.001), showing the highest enrichment among the measured genetic factors.
While TG-associated rare variants and common SNPs are both found in statistical excess in severe HTG patients of different ancestral backgrounds, the overall genetic profiles of each ancestry group were distinct.
易患严重高甘油三酯血症（HTG）的人，其血浆甘油三酯（TG）水平≥10mmol/L（880mg/dL），这是由五个参与 TG 代谢的基因中的杂合罕见变异以及与 TG 水平相关的许多常见单核苷酸多态性（SNP）共同导致的。
迄今为止，这些遗传易感因素主要在欧洲血统的严重 HTG 患者中得到了全面评估。在这里，我们将分析范围扩大到东亚和西班牙裔血统的 HTG 患者。
对分别来自欧洲、东亚和西班牙裔血统的 336、63 和 199 例严重 HTG 患者的基因组 DNA 进行了靶向下一代测序面板评估，以筛选：1）LPL、APOA5、APOC2、GPIHBP1 和 LMF1 中的罕见变异；2）使用多基因评分量化的常见、小到中等效应 SNPs；3）常见的、大效应多态性 APOA5 p.G185C 和 p.S19W。
虽然高多基因评分个体的比例相似，但不同血统的罕见变异携带者的频率不同。与同血统对照相比，西班牙裔患者最有可能携带罕见变异（OR=5.02；95%CI 3.07-8.21；p<0.001），而欧洲患者则最不可能（OR=2.56；95%CI 1.58-4.13；p<0.001）。APOA5 p.G185C 多态性仅存在于东亚人中，与对照组相比，患者中明显富集（OR=10.1；95%CI 5.6-18.3；p<0.001），在测量的遗传因素中显示出最高的富集。
虽然不同祖先背景的严重 HTG 患者中都存在与 TG 相关的罕见变异和常见 SNP，但每个血统组的总体遗传特征都不同。
