Unidad de Lípidos, IIS Aragón, CIBERCV, Hospital Universitario Miguel Servet, Avda. Isabel La Católica 1-3, 50009, Zaragoza, Spain.
Universidad de Zaragoza, Zaragoza, Spain.
Sci Rep. 2021 Mar 26;11(1):7002. doi: 10.1038/s41598-021-86384-y.
Angiopoietin-like 3 (ANGPTL3) plays an important role in lipid metabolism in humans. Loss-of-function variants in ANGPTL3 cause a monogenic disease named familial combined hypolipidemia. However, the potential contribution of ANGPTL3 gene in subjects with familial combined hyperlipidemia (FCHL) has not been studied. For that reason, the aim of this work was to investigate the potential contribution of ANGPTL3 in the aetiology of FCHL by identifying gain-of-function (GOF) genetic variants in the ANGPTL3 gene in FCHL subjects. ANGPTL3 gene was sequenced in 162 unrelated subjects with severe FCHL and 165 normolipemic controls. Pathogenicity of genetic variants was predicted with PredictSNP2 and FruitFly. Frequency of identified variants in FCHL was compared with that of normolipemic controls and that described in the 1000 Genomes Project. No GOF mutations in ANGPTL3 were present in subjects with FCHL. Four variants were identified in FCHL subjects, showing a different frequency from that observed in normolipemic controls: c.607-109T>C, c.607-47_607-46delGT, c.835+41C>A and c.*52_*60del. This last variant, c.*52_*60del, is a microRNA associated sequence in the 3'UTR of ANGPTL3, and it was present 2.7 times more frequently in normolipemic controls than in FCHL subjects. Our research shows that no GOF mutations in ANGPTL3 were found in a large group of unrelated subjects with FCHL.
血管生成素样 3（ANGPTL3）在人类脂质代谢中发挥重要作用。ANGPTL3 基因的功能丧失性变异可导致一种单基因疾病，称为家族性混合型高脂血症。然而，ANGPTL3 基因在家族性混合型高脂血症（FCHL）患者中的潜在作用尚未得到研究。因此，本研究旨在通过鉴定 FCHL 患者 ANGPTL3 基因中的获得性功能（GOF）遗传变异，来研究 ANGPTL3 基因在 FCHL 发病机制中的潜在作用。在 162 名无血缘关系的严重 FCHL 患者和 165 名血脂正常对照者中，对 ANGPTL3 基因进行测序。利用 PredictSNP2 和 FruitFly 预测遗传变异的致病性。比较 FCHL 患者中鉴定出的变异频率与血脂正常对照组和 1000 基因组计划（1000 Genomes Project）中描述的频率。在 FCHL 患者中未发现 ANGPTL3 的 GOF 突变。在 FCHL 患者中发现了 4 种变异，其频率与血脂正常对照组不同：c.607-109T>C、c.607-47_607-46delGT、c.835+41C>A 和 c.*52_*60del。最后一个变异 c.*52_*60del 是 ANGPTL3 3'UTR 中的 microRNA 相关序列，在血脂正常对照组中的频率比 FCHL 患者高 2.7 倍。本研究表明，在一组无血缘关系的严重 FCHL 患者中未发现 ANGPTL3 的 GOF 突变。
