ASGR1 - a new target for lowering non-HDL cholesterol

Abstract

Non-HDL cholesterol (non-HDL-C) has been introduced as an alternative cardiovascular (CV) risk marker and a secondary therapeutic target in patients with combined hyperlipidemia, diabetes mellitus, metabolic syndrome, or chronic kidney disease. An important genetic study on the Icelandic population has recently identified a strong link between a new gene – ASGR1 (for asialoglycoprotein receptor) – mutation, plasma non-HDL-C levels, and coronary heart disease (CHD). Heterozygous carriers of a rare noncoding 12-base-pair (bp) deletion (del12 deletion) in intron 4 of ASGR1 had a 13.6 mg/dl lower level of non-HDL-C and a 34% lower risk of CHD than non carriers. The cardioprotective effect of ASGR1 loss-of-function is surprisingly larger than predicted by its effect on the levels of non-HDL-C, which suggests that the atheroprotective effects of del12 mutation go beyond the lowering of serum cholesterol levels. This has shed some light on a new path – the sialylation pathway – possibly leading to a novel therapy that neutralize ASGR1 for heart disease prevention and treatment.