Some people with high levels of ‘good’ high density lipoprotein cholesterol (HDL-C) are at increased risk of coronary heart disease, contrary to earlier evidence that people with more HDL-C are usually at lower heart disease risk. This finding comes from an international study involving researchers at the University of Cambridge, funded by the British Heart Foundation (BHF).

Large-scale collaborative research like this paves the way for further studies of rare mutations that might be significantly increasing people’s risk of a deadly heart attack

Adam Butterworth

The discovery, published today in Science, could move researchers away from potentially ineffective HDL-raising drugs to treat coronary heart disease, and lead to the development of new treatments, helping to reduce their risk of heart attack.

The researchers studied people with a rare genetic mutation in the SCARB1 gene, called the P376L variant, which causes the body to have high levels of ‘good’ HDL-C. High levels of ‘good’ cholesterol are commonly associated with reduced risk for coronary heart disease. Challenging this view, the researchers unexpectedly found that people with the rare mutation, who had increased levels of HDL-C, had an 80 per cent increased relative risk of the disease – a figure almost equivalent to the increased risk caused by smoking.

Coronary heart disease is responsible for nearly 70,000 deaths every year, almost entirely through heart attacks, making it the UK’s single biggest killer. The disease involves the build-up of fatty material, or plaque, in the coronary artery walls. If large quantities accumulate in the vessel walls, blood flow to the heart can become restricted or blocked, increasing risk of a heart attack.

The international team of scientists included BHF-funded researchers Professor Sir Nilesh Samani at the University of Leicester and Professor John Danesh at the University of Cambridge. They initially looked at the DNA of 328 individuals with very high levels of HDL-C in the blood and compared them to 398 people with relatively low HDL-C. As the P376L variant they found was so rare, they then looked at its effects on HDL-C and heart disease in more than half a million additional people.

Dr Adam Butterworth, from the Cardiovascular Epidemiology Unit,  University of Cambridge,  and co-investigator of this study, said: “We found that people carrying a rare genetic mutation causing higher levels of the so-called ‘good’ HDL-cholesterol are, unexpectedly, at greater risk of heart disease. This discovery could lead to new drugs that improve the processing of HDL-C to prevent devastating heart attacks.

“Large-scale collaborative research like this paves the way for further studies of rare mutations that might be significantly increasing people’s risk of a deadly heart attack. These discoveries also give researchers the knowledge we need to develop better treatments.”

Professor Peter Weissberg, Medical Director at the BHF, added said: “This is an important study that sheds light on one of the major puzzles relating to cholesterol and heart disease, which is that despite strong evidence showing HDL-C reduces heart disease risk, clinical trials on the effects of HDL-C-raising drugs have been disappointing.

“These new findings suggest that the way in which HDL-C is handled by the body is more important in determining risk of a heart attack than the levels of HDL-C in the blood. Only by understanding the underlying biology that links HDL-C with heart attacks can we develop new treatments to prevent them. These unexpected findings pave the way for further research into the SCARB1 pathway to identify new treatments to reduce heart attacks in the future.”

Additional funding for the study in the USA came from the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institute of Health.

Reference
Zanoni, P et al. Rare Variant in Scavenger Receptor BI raises HDL Cholesterol and Increases Risk of Coronary Heart Disease. Science; 10 Mar 2016; DOI: 10.1126/science.aad3517

Adapted from a press release from the British Heart Foundation


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