Abstract
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.
Highlights
Angiopoietin-like 3 (ANGPTL3) plays an important role in lipid metabolism in humans
Different studies in families with hypolipemia and in general population have reported that loss-of-function (LOF) variants in ANGPTL3 gene are associated with decreased plasma levels of triglycerides (TG), low-density lipoprotein cholesterol (LDLc) and high-density lipoprotein cholesterol (HDLc)[4]
The APOE genotype distribution was homogenous between both cohorts, being E3/3 genotype the most frequent in both groups, E3/2 genotype had a lower frequency in familial combined hyperlipidemia (FCHL) subjects (5.56%) in contrast to normolipemic subjects (15.2%)
Summary
Angiopoietin-like 3 (ANGPTL3) plays an important role in lipid metabolism in humans. Loss-offunction variants in ANGPTL3 cause a monogenic disease named familial combined hypolipidemia. 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. 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. Different studies in families with hypolipemia and in general population have reported that loss-of-function (LOF) variants in ANGPTL3 gene are associated with decreased plasma levels of triglycerides (TG), low-density lipoprotein cholesterol (LDLc) and high-density lipoprotein cholesterol (HDLc)[4]. Exclusion secondary causes: Secondary causes of hypercholesterolemia Overweight or obesity (BMI ≥ 27.5 Kg/m2) Poorly controlled type 2 diabetes (HbA1c >8%) Hemochromatosis Renal disease with glomerular filtraƟon rate < 30 mL/min and/or macroalbuminuria Liver disease (alanine transaminase > 3 Ɵmes upper normal limit) Hypothyroidism (thyroid-sƟmulaƟng hormone > 6 mIU/L) Pregnancy or estrogen treatment Autoimmune diseases Treatment with protease inhibitors Alcohol consumpƟon >30 grams per day Absence of first degree relaƟves with hyperlipidemia
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