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Gene mutation carriers get equivalent of lifetime's anti-cholesterol treatment

18 November 2014
Appeared in BioNews 780

An inactive copy of a gene associated with cholesterol levels can reduce the risk of a heart attack, according to a study.

The researchers estimated that only around one in 650 people may carry the mutations identified as reducing the gene's activity, however.

Combining genetic data from over 100,000 people, researchers from a number of institutions, including the Broad Institute and Massachusetts General Hospital, found that a mutated, inactive copy of NPC1L1 was associated with lower levels of low-density lipoprotein (LDL) cholesterol. They also found that people with a single working copy of the gene had a lower risk of heart disease by up to 50 percent. High LDL cholesterol is a major risk factor in the development of heart disease.

'This analysis demonstrates that human genetics can guide us in terms of thinking about appropriate genes to target for clinical therapy. When people have one copy of a gene not working, it's a little like taking a drug their entire lives that is inhibiting this gene,' explained first author Dr Nathan Stitziel, a cardiologist at Washington University School of Medicine.

After sequencing the exome of 20,000 patients from previous large-scale clinical trials, the researchers found 15 separate rare mutations that appeared to disrupt the NPC1L1 gene.

The researchers then looked at data from an additional 90,000 patients and found that mutations correlated with a lower risk of coronary heart disease compared with non-carriers. Only 82 people from a total of 113,000 trial participants had one working copy of the NPC1L1 gene, but they were found to have around half the risk of heart disease than people with two working copies. Most people have two active copies of the NPC1L1 gene.

Senior author Professor Sekar Kathiresan, of the Broad Institute and director of preventive cardiology at the Massachusetts General Hospital, noted: 'One of the key concepts here is that it may not be how you lower LDL or how low you take LDL but rather how long the LDL is lowered. We should think about LDL like we do smoking. Smoking is typically quantified as "pack-years", a product of the number of years smoked times the number of packs per day. The concept to stress may be "LDL-years"'.

At around a ten percent reduction, the effect of the mutation in reducing LDL levels is comparable to ezetimibe treatment. This FDA-approved drug reduces LDL levels by blocking the absorption of cholesterol in the gut, inhibiting the activity of the NPC1L1 protein.

Although the drug has been shown to lower cholesterol, the effect that ezetimibe has on reducing the risk of a heart attack has not yet been shown. However, the finding that mutations of NPC1L1 reduce the risk of coronary heart disease increases the probability that a drug inhibiting NPC1L1 may do the same, Dr Stitziel explained.

Professor Jeremy Pearson, from the British Heart Foundation, said: 'Whether ezetimibe can do so is currently being tested in a large trial, whose results are eagerly awaited.' The ongoing phase III study is evaluating ezetimibe will reduce the risk of recurrent cardiovascular events in patients who had an acute attack. The trial results will be presented on 17 November at the annual meeting of the American Heart Association.

The NPC1L1 gene study was published in the New England Journal of Medicine.

Carriers of NPC1L1 Inactivating Mutations Have Lower Coronary Heart Disease Risk, Researchers Say
genomeweb |  13 November 2014
Defective NPC1L1 gene found to protect against heart disease
Broad Institute (press release) |  12 November 2014
Errors in single gene may protect against heart disease
EurekAlert! (press release) |  12 November 2014
Gene error 'reduces heart attack and cholesterol risk'
BBC News |  13 November 2014
Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease
New England Journal of Medicine |  12 November 2014
Newly Identified Gene Mutations Act Like A Lifetime Of Treatment With Merck Cholesterol Drug
Forbes |  13 November 2014
Rare Mutation Mimicked by Merck’s Zetia Cuts Heart Risk
Bloomberg |  13 November 2014
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