Variants in ASGR1 linked to reduced CAD risk

Given that non-HDL cholesterol encompasses all cholesterol-containing proatherogenic lipoproteins, it is believed to be a better predictor of coronary artery disease (CAD) risk than LDL cholesterol alone. To identify new genetic variants that affect the levels of non-HDL cholesterol, Nioi and colleagues sequenced the genome of 2,636 individuals from Iceland, and found a noncoding 12-base-pair deletion in intron 4 of ASGR1, a major subunit of the asialoglycoprotein receptor that can mediate the endocytosis and degradation of numerous desialylated glycoproteins. Heterozygous carriers of this ASGR1 variant had a lower level of non-HDL cholesterol (P = 1.0×10⁻¹⁶), in addition to a 34% lower risk of CAD (95% CI 21–45, P = 4.0×10⁻⁶). In a larger set of sequenced samples from the Icelandic individuals, another loss-of-function ASGR1 variant associated with lower non-HDL cholesterol levels was identified. According to the investigators, “these variants disrupt ASGR1 function and represent a link between the sialylation pathway and atherosclerotic diseases.