Recent publications on Residual Risk

This study, involving data from 2636 Icelandic subjects, focused on the ASGR1 gene, which codes for a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. Researchers identified two loss-of-function ASGR1 variants (del12 and p.W158X) that had significant effects on non-HDL-C. When these data were imputed to the Icelandic population, it was shown that individuals who were heterozygous for the del12 mutation (0.8% of the study population) had 15.3 mg/dL (0.40 mmol/L) lower non-HDL-C levels than noncarriers. Furthermore, these heterozygous individuals also had a 34% reduction in risk for coronary artery disease (p=4.0×10?6). Carriers also had lower triglyceride levels, although the effect was weaker than for non-HDL-C. The other loss-of-function variant (p.W158X, found in 1 in 1,850 people) was associated with 24.9 mg/dL decrease in non-HDL-C levels and 35% decrease in coronary risk, although this was not statistically significant (p=0.24). Replication testing in 42,524 case patients and 249,414 controls from five European ancestry populations confirmed the findings. These variants, which disrupt ASGR1 function, therefore represent a link between the sialylation pathway and atherosclerotic disease. In an accompanying editorial,1 Professor Anne Tybjaerg-Hansen (University of Copenhagen, Denmark) suggested that the findings may offer new therapeutic potential, although elucidation of the underlying mechanism(s) is needed. Indeed, given the magnitude of the effects of coronary risk versus lipids compared with other loss-of-function variants (such as PCSK9), this might suggest that the mutation also impacts non-lipid pathways, such as those involving inflammatory mediators. Research is ongoing to identify the target molecule with the aim of developing novel therapies.
 
1. Tybjærg-Hansen A. The sialylation pathway and coronary artery disease. N Engl J Med. 2016 May 18. [Epub ahead of print].