Abstract 16767: Mutations in the Gene Encoding for Polypeptide N-acetylgalactosaminyltransferase 2 are Associated with High Levels of Plasma High-Density Lipoprotein Cholesterol
GALNT2 encoding polypeptide N-acetylgalactosaminyltransferase 2 (GalNAc-T2) was recently identified in genome-wide association studies to be involved in high-density lipoprotein (HDL) metabolism. Subsequent studies into GALNT2 variation in cohort studies as well as overexpression and silencing approaches in mice have provided supportive evidence that this enzyme, which catalyzes O-linked glycosylation of Thr and Ser residues of target proteins in the Golgi, indeed regulates HDL cholesterol levels. The current study establishes a role for GalNAc-T2 in human lipid metabolism through studies in individuals with high HDL cholesterol levels and their families. Mutations in the promoter (n=1), coding (n=3) and non-coding regions (n=1) of GALNT2 were identified in 5 individuals with HDL cholesterol levels above the 95th percentile for age and gender (all heterozygotes). Through expansion of the families of 2 probands with a same nonsynonymous missense mutation in GALNT2, we recruited 8 heterozygotes for and 14 unaffected family members. Carriers presented with increased HDL cholesterol levels (73.1±10 vs. 53.0±23 mg/dl, p<0.01) and decreased triglyceride levels (79.7 (IQR 65-95) vs. 92.1 (IQR 66-117) md/dl, p<0.05). In addition, heterozygotes showed unchanged activities of lecithin:cholesterol acyltransferase (an O-linked glycosylated enzyme involved in HDL metabolism) when an exogenous substrate was used. Pilot data furthermore indicate that the respective missense mutation is functional and that heterozygotes may exhibit improved post-prandrial triglyceride metabolism (studies are ongoing). These data support a direct role of GalNAc-T2 in human lipid metabolism.
- © 2010 by American Heart Association, Inc.