A Gene Linked to Lower Risks of Heart Attacks
A rare mutation discovered at Amgen subsidiary deCODE Genetics is associated with a 34 percent lower risk of coronary artery disease. Amgen scientists aim to turn this insight into a new type of heart drug, which might complement lipid-lowering drugs by addressing other potential risk factors for heart disease.
While cholesterol levels are strongly linked to the risk for heart disease, it also appears that cholesterol by itself doesn’t tell the whole story. There are people with high levels of bad cholesterol who never develop heart disease, and people with lower-than-average cholesterol levels can still suffer heart attacks. This suggests that blood lipids are not the sole risk factor for heart disease, and that other factors may also contribute to atherosclerosis. Identifying these other contributing biological pathways could lead to entirely new types of cardiovascular drugs.
In a study based on genome, cholesterol, and heart disease data from 700,000 people in seven countries, researchers found that a rare mutation in a gene called ASGR1 reduced the risk for coronary artery disease by 34 percent.1 The mutation also decreased non-HDL cholesterol (total cholesterol minus good cholesterol) by 15.3 milligrams per deciliter, or roughly 10 percent. While this decline is significant, the mutation appears to confer greater protection against coronary heart disease than can easily be accounted for by the reduction in cholesterol alone.1,2 This suggests the mutation affects another yet to be identified risk factor.
What is ASGR1?
ASGR1 is a gene that contains the DNA code for making asialoglycoprotein receptor 1, a major subunit of a receptor found mostly on liver cells. ASGR1 and ASGR2 combine to form the asialoglycoprotein receptor (ASGPR).
The receptor binds to glycoproteins–proteins with carbohydrate chains attached to them. More specifically, it binds to glycoproteins that have lost the sialic acid group from their carbohydrate chain, exposing other carbohydrates that attach to the receptor.
The Role of ASGR1
This receptor binds to asialylated glycoproteins and pulls them inside the liver cell, where the proteins are degraded in compartments called lysosomes. The receptor then returns to the cell surface to continue performing its function.
Known binding partners of ASGPR include alkaline phosphatase, a liver enzyme, and haptocorrin, which helps transport vitamin B12 through the stomach.¹ It is possible that ASGPR has other binding partners that have not been characterized yet.¹
The rare variant in ASGR1 is characterized by a deletion of 12 base pairs of DNA in the non-coding region of the gene.¹ That leads, in turn, to a deletion of 22 base pairs in the messenger RNA that makes protein.¹
The end result is a truncated version of ASGR1 protein and a loss of the receptor’s normal function.¹
People with heterozygous mutation in ASGR1 have one normal copy of the gene and one non-functioning copy.
Impact of the Mutation
By reducing the number of functioning ASGP receptors, the del12 mutation increases the level of asialylated proteins that would otherwise have been degraded by the receptor. The mutation also decreases levels of non-HDL cholesterol, including LDL (“bad” cholesterol), through a mechanism that is being investigated.
Impact on Heart Disease
Individuals who carry the del12 mutation appear to have a 34 percent lower-than-average risk of coronary artery disease.¹ Men and women who carry this gene variant are significantly less likely to experience a first heart attack as they age.¹ Carriers have a life span that is more than a year longer on average than non-carriers.¹
The mutation’s impact on heart disease risk is larger than one would predict based solely on its impact on non-HDL cholesterol.¹ This suggests that the mutation also impacts other risk factors for heart disease.
1. Nioi, P, Sigurdsson, A, Thorleifsson, G, et al. Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease. New Eng J Med. 2016;374(22): 2131-2141.
2. Tybjærg-Hansen, A. The Sialylation Pathway and Coronary Artery Disease. New Eng J Med.2016;374(22):2169-2171.