Key result
No gain-of-function mutations in the ANGPTL3 gene were found in subjects with familial combined hyperlipidemia, indicating it does not play a substantial role in the disease etiology.
Why the study?
The potential contribution of the ANGPTL3 gene and gain-of-function variants to the aetiology of familial combined hyperlipidemia had not been studied.
Do gain-of-function variants in the ANGPTL3 gene contribute to the etiology of familial combined hyperlipidemia?
Case-Control (n=327)
No
Do gain-of-function variants in the ANGPTL3 gene contribute to the etiology of familial combined hyperlipidemia?
Absolute Event Rate: 0% vs 0%
ANGPTL3 GOF screening is not indicated in FCHL workup; leaves open regulatory-variant effects and challenges a monogenic etiology.
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. To study the gain-of-function (GOF) genetic variants in the ANGPTL3 gene in FCHL subjects and to establish the potential contribution of ANGPTL3 in the aetiology of FCHL. 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 the1000 Genomes Project. No GOF mutations in ANGPTL3 was present in subjects with FCHL. Four variants were identified in FCHL subjects, showing a frequency different 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.
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Bea et al. (2021) conducted a case-control in Familial combined hyperlipidemia (n=327). ANGPTL3 gene variants vs. Normolipemic controls was evaluated on Gain-of-function mutations in ANGPTL3. No gain-of-function mutations in the ANGPTL3 gene were found in subjects with familial combined hyperlipidemia, indicating it does not play a substantial role in the disease etiology.
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