Variant ASGR1 and Reduced Risk of Coronary Artery Disease

Study Questions:

What is the association of ASGR1 sequence variation with lipid levels and risk for coronary artery disease (CAD)?


Sequence variants, identified from the whole genomes of 2,636 Iceland subjects, were then imputed into genomes of 398,000 Icelanders and tested for associations with non–high-density lipoprotein (HDL) cholesterol levels. Replication testing was performed in two European populations and the effects of a loss-of-function variant were tested for CAD risk in 42,524 cases and 249,414 controls.


A rare noncoding deletion in intron 4 of the gene for a subunit of the asialoglycoprotein receptor (ASGR1) was associated with lower levels of non-HDL cholesterol (15.3 mg/dl reduction in heterozygous carriers) and a 34% lowered risk for CAD. An additional loss-of-function variant in this gene was also associated with lower non-HDL cholesterol.


The authors concluded that haploinsufficiency of ASGR1 is associated with reduced non-HDL cholesterol and reduced risk for CAD.


ASGR1 is a receptor involved in the endocytosis and degradation of desialylated glycoproteins. This study adds important insight into additional mechanisms involved in lipoprotein regulation. Importantly, this study also demonstrates that carriers of a loss-of-function ASGR1 variant show reduced CAD risk. The mechanism for the particularly impressive CAD risk reduction may be more complicated than enhanced apolipoprotein B–containing lipoprotein clearance, as other pathways are affected by this gene. While a greater understanding of the mechanism(s) for CAD risk reduction will be important, ASGR1 appears to represent another success story of large-scale genetics and a new therapeutic target for CAD risk reduction.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins

Keywords: Apolipoproteins B, Asialoglycoprotein Receptor, Asialoglycoproteins, Cholesterol, HDL, Coronary Artery Disease, Dyslipidemias, Endocytosis, Haploinsufficiency, Introns, Lipoproteins, Lipoproteins, HDL, Primary Prevention, Risk Reduction Behavior

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