Rare mutation can reduce heart disease risk by 34%

"Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease"

N Engl J Med 374;22

It is only very recently in human history that we have had the power to begin to explore human genetics. Without the technology to cheaply sequence DNA, without the powerful computers and sophisticated statistical methods needed to analyze huge amounts of genetic data, it was impossible for us to even begin to ask fundamental questions about the genetic factors that contribute to human life and disease.

The invention of these technologies has lead to an explosion of studies on human genetics, particularly through the use of a type of study called genome-wide association studies (or GWAS).

An example of a genetic difference, or variation

In these studies the DNA of large numbers of people is sequenced and compared to the sequences of other people. 

Most of our DNA is identical, as we all belong to the same species, but there are many places where two or more people have 'differences' in their DNA sequence.

These differences can be called many things - mutations, polymorphisms, variants - but all these words simply refer to a difference in DNA sequence that exists in two or more individuals.

Scientists can test if the presence or absence of different DNA variants associates strongly with different 'traits' like height, smoking behavior and risk for inflammatory bowel disease. This requires conducting very large case-control trials that can involve collecting DNA and clinical information from hundreds of thousands of subjects.

Imagine that you had a study where 30,000 subjects had a rare mutation and 150,000 controls didn't have that mutation. Because the sample population is so large and diverse, if you observe that the group with the mutation differs consistently from the control group in some trait, you can conclude that is quite likely that the mutation is responsible for this difference. This is the basis of a GWAS study.

A recent paper from Kári Stefánsson's group at deCODE genetics has identified a rare genetic mutation that is associated with a reduced risk for heart disease.

They identified a rare mutation in a gene called asialoglycoprotein receptor 1 (ASGR1) - in their study population, 1 in a 120 people were heterozygous for this rare mutation. In a large analysis involving 42,524 cases with heart disease and 249,414 controls, the team showed that carrying the rare ASGR1 mutation can reduce the risk of heart disease by up to 34%. 

Survival curves comparing morality between
carriers and noncarriers of the ASGR1 mutation
(from the paper)

So how can a mutation in this gene protect someone from heart disease? This is an important question - cardiovascular disease is the leading cause of death across the globe. More people will die annually from cardiovascular disease than any other cause.

A single mutation that can reduce the risk of heart disease by such a large amount has enormous implications for medicine. Scientists can now study the function of the non-mutant ASGR1 gene in cardiovascular physiology, and try and understand how a mutation in this gene can protect from heart disease.

The mutation identified in this study is a 12 base-pair long deletion in an intron of the ASGR1 gene. It leads to a frameshift mutation in the gene, so that the protein that it encodes is truncated. The mutant protein is not stable - because it is a truncated mutant that could harm the cell, it is targeted by the proteasome, a cell organelle that is used to destroy mutant and waste proteins. Thus, the mutation leads to a total absence of the gene from the organism.

The study did not identify people who were homozygotes for the mutation, presumably because a human being that totally lacked this essential gene would die. Instead, the study identified heterozygotes who have one functioning copy and one broken mutant. These individuals are haploinsufficient for ASGR1 - they have lower amounts of ASGR1 protein in their cells than most of the population.

At this point we do not fully understand how the mutation protects people from heart disease - future studies combining genetics and cardiac physiology in mouse models of human disease are needed to fully answer this question.

Individuals with the mutation were also found to have lower levels of non-HDL cholesterol (or "bad" cholesterol) in their blood. While this probably explains part of the protective effect of the mutation, it is unlikely to be the complete story. It is also not yet understood how this mutation leads to lowered levels of bad cholesterol.

The figure below from the paper compares the effects of different rare mutations (using data collected across multiple large studies) on bad cholesterol levels (x-axis) and heart disease risk (y-axis) in human populations.

Each point represents a single mutation. Mutations in the upper half of the dotted axes increase the risk of heart disease, while those in the lower half reduce this risk. ASGR1, the gene identified in this study, is highlighted in blue.





Previous to this study, other mutations in genes such as APOC3 had already been identified that reduce the levels of bad cholesterol and reduce heart disease risk. But the ASGR1 mutation identified in this study is different - it leads to a greater reduction in heart disease risk than any other previously identified mutation, but it leads to a milder reduction in bad cholesterol levels.

So reduced bad cholesterol levels can't be the entire story - there are other unknown mechanisms by which the mutation protects from heart disease.

Understanding these mechanisms could lead to new therapies and interventions for cardiovascular disease, the leading cause of death across the globe.

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