English abstract
Hypertriglyceridemia (HTG) is a risk factors of cardiovascular disease. Impaired clearance of triglyceride rich lipoproteins, VLDL and chylomicrons, as well as excessive intake and synthesis, are the leading causes of HTG. Mutations in at least 6 different genes cause familial hypertriglyceridemia, namely lipoprotein lipase (LPL), apolipoprotein C-II (APOC2), apolipoprotein A-5 (APOA5), glycosylphosphatidylinositol anchored high density lipoprotein binding protein (GPIHBP1), lipase maturation factor 1 (LMF1) and apolipoprotein E (ApoE) genes. Cases with severe hypertriglyceridemia are managed in the lipid clinic at Sultan Qaboos
University Hospital (SQUH). They are diagnosed as familial hypertriglyceridemia based on clinical criteria which might not be accurate and definitive.
Aim: In this study, we investigate the genetic causes of familial hypertriglyceridemia among clinically diagnosed cases to give proper counseling and avoid future born of affected child, as well as correlate the mutations with lipase activity and LPL expression level.
Method: The study included 12 affected individuals from lipid clinic at SQUH, that are diagnosed clinically, having familial hypertriglyceridemia with TGs level above 11.2 mmol/L. Seventeen healthy relatives were recruited as study control group. Two blood samples were collected from all individuals under study. IonTorrent next generation sequencing was performed the panel of 6 genes and VCF files were annotated using wANNOVAR tool. To study the pathogenicity of genetic defects, LPL expression level was estimated by immunoblotting and total lipase activity wasmeasured using colourimetric assay kit.
Results: Our study revealed 3 novel pathogenic variants in LPL gene (p.M328T, p.H229L and p.S286G) and a novel frameshift mutation in ApoE gene (p.L159fs). p.M328T, p.S286G and p.L159fs according to mutation prediction algorithms are damaging.
Conclusion: The study highlights the genetic determinants of familial hypertriglyceridemia among clinically diagnosed individuals at SQUH. The mutations detected in LPL gene have loss of function effect and p.L159fs produces defective ApoE protein where all of them contribute to improper clearance of triglyceride rich lipoproteins from the circulation leading to hypertriglyceridemia. Family counseling is recommended for the affected families.
