Genetic Mutation that Protects Against Heart Disease

May 24, 2016
Genetic Mutation that Protects Against Heart Disease
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Identifying the genetic backgrounds that provide innate protection to maladies such as cancer, infectious diseases, or cardiovascular disorders is paramount to developing appropriate therapies to treat the majority of afflicted patients who suffer from these ailments. Now, an international team of researchers has focused their attention on elucidating the complex genetics underlying heart disease and found that just less than 1% of the population is naturally protected against developing chronic coronary artery diseases.       

Investigators took genetic samples from 292,000 participants of European origin. Applying advanced gene sequencing techniques, the researchers located an area—a deletion—in the human genome that lacked 12 DNA building blocks in 0.8% of the participants.

“We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders,” the author wrote. “We tested for association between these imputed variants and non-HDL [high-density lipoprotein] cholesterol levels in 119,146 samples. ...We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene.”

The findings from this study were published recently in the New England Journal of Medicine in an article entitled “Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.”

Subsequent cell experiments revealed that due to the deletion, the asialoglycoprotein receptor 1 (ASGR1) gene is unable to establish the normal structure and function of its translated protein. This receptor protein binds certain sugars and plays a major role in cholesterol metabolism and is potentially related to vascular inflammation—which often leads to the development of arteriosclerosis in coronary arteries.

“We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins,” the authors stated. “The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. ...ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease.”

"What's spectacular about the discovery is the fact that individuals with this rare and particular mutation have a lower level of cholesterol in their blood, and their risk of developing arteriosclerosis is 34% less,” explained Oluf Pedersen M.D., D.M.Sc., director at the Novo Nordisk Foundation Center for Basic Metabolic Research within the University of Copenhagen. “In other words, just under 1% of the European population is fortunate to have been born with a mutation that decreases their cholesterol levels and thus to a certain extent protects them from developing coronary atherosclerosis."

Dr. Pedersen continued, concluding that "the mutated protein is expressed in a part of human biology, which we have not previously been focused on in our attempts to understand the mechanisms behind arteriosclerosis. This unexpected finding will undoubtedly result in many researchers examining the underlying biological systems very thoroughly—hoping to utilize this new knowledge to develop new preventive measures and treatments for cardiovascular diseases."