Rare mutation may protect against heart disease

A rare genetic mutation reduces the risk of having a heart attack by one-third, a study has found.

The mutation, which substantially lowers levels of non-HDL cholesterol – a marker for heart-disease risk – is already being investigated as potential drug target for preventing heart disease.

‘[This is] an important and previously unknown mechanism for modulating non-HDL cholesterol and risk of the most common and deadly forms of heart disease,’ said Dr Kári Stefánsson, founder and CEO of deCODE Genetics, who led the research. ‘We know we have put our finger on something fundamental when we find a single variant that confers on carriers an average one year of extra lifespan,’ he added.

The study, published in the New England Journal of Medicine, matched the genomic data of around 400,000 Icelanders against their medical records. The team found that fewer than one percent of these individuals had a loss-of-function mutation that was associated with significantly lower levels of non-HDL cholesterol. Carriers of the mutation were also 34 percent less likely to develop heart disease, and lived on average one year longer. The researchers could not find any adverse effects of having this mutation.

The same correlation cropped up when they looked at the genomes of over 300,000 people of European ancestry, including populations from the Netherlands, Denmark, Germany, New Zealand, the UK and the USA.

The mutation they identified was in the gene ASGR1. Although the researchers do not yet know how the mutation results in a reduction in the risk of heart disease, Amgen – the technology giant that bought deCODE Genetics in 2012  – is already developing drugs to mimic its protective effect.

Researchers found a mutation with a similar effect over a decade ago, and Amgen recently developed a drug based on it. The drug was approved by the US Food and Drug Adminstration last year. But Dr Stefánsson believes that this new drug target may be even more effective as he says it reduces heart-disease risk by more than would be expected given its effect on cholesterol alone. ‘This is a genetic discovery that is pointing to the possibility of manipulating something other than just blood lipids,’ he told Nature News. ‘We have no drugs, really, that affect the risk of coronary heart disease that work on alternative mechanisms.’

However, Professor Harlan Krumholz, a cardiology researcher at Yale University in Connecticut, is unconvinced by this claim. ‘This study is far from identifying an alternative mechanism of risk reduction for a variant associated with non-HDL reduction,’ he told Nature News.