Abstract 14741: Genetic Defects in Protein Glycosylation as a Cause of Dyslipidemia
Aim: In most of our patients, we cannot reach adequate risk reduction with current treatments for dyslipidemia. This stresses the need for a more accurate understanding of lipid metabolism in order to identify novel targets to improve our treatment. Recently our group described a genetic mutation in GALNT2 causing attenuated glycosylation of apoCIII and increased plasma HDL-cholesterol, demonstrating the first dyslipidemia caused by a genetic defect in the glycosylation of proteins. We hypothesized that other genetic disorders of glycosylation could lead to dyslipidemia as well.
Methods: Firstly, genome-wide association studies (GWAS) were analyzed for links between glycosylation genes and plasma lipid levels. Secondly, a subgenome of genes known to be involved in congenital disorders of glycosylation (CDG) was analyzed in patients with extremely high and low HDL-cholesterol levels. Thirdly, lipid metabolism in patients with congenital disorders of glycosylation was studied. When a link was identified, a range of functional studies was performed to identify linking molecular mechanisms.
Results: Firstly, GWAS linked variation in glycosylation genes GALNT2, B3GALT4 and B4GALT4 to plasma lipids. Secondly, we have identified multiple non-sense and missense variants in glycosylation genes in patients with extremely high and low HDL-cholesterol. Thirdly, we found strongly increased levels of HDL-cholesterol, aberrantly glycosylated CETP and decreased CETP activity in a patient with a characterized genetic defect of a specific galactosyltransferase glycosylation enzyme, B4GalT1. Lastly, we systematically analyzed several patients with PMM2- and ALG6-CDG, and found decreased levels of total cholesterol, LDL-cholesterol and apolipoprotein B.
Conclusions: In conclusion, our studies indicate specific physiological functions of protein glycosylation in lipid metabolism and may indicate completely novel targets for better treatment of dyslipidemia
- © 2013 by American Heart Association, Inc.