Rare mutation turns 'good' cholesterol bad

A rare genetic mutation that causes high levels of 'good' cholesterol also appears to block its positive effects, increasing the risk of heart disease by 80 percent.

The study may help to explain why drugs designed to increase levels of good cholesterol have failed to work.

'We had always believed that good cholesterol is associated with a lower risk of heart disease. This is one of the first studies to show that some people that have high levels of "good" cholesterol actually have a higher risk of heart disease, so it challenges our conventional wisdom about whether 'good' cholesterol is protecting people from heart disease or not,' Dr Adam Butterworth of the University of Cambridge, one of the study authors, told BBC News.

They are two types of cholesterol – high density lipoprotein (HDL) and low density lipoprotein, (LDL). HDL is often referred to as 'good' cholesterol because it removes fatty, harmful LDL – 'bad' cholesterol – from cells, transporting it to the liver for processing. In doing so, HDL reduce the risk of coronary heart disease, so high levels of good cholesterol have been seen as an indicator of low heart disease risk.

However, drugs that increase levels of HDL aren't always effective in reducing the risk of heart disease. The present study, published in Science, gives some insight into why this might be.

The researchers identified 328 individuals with abnormally high levels of HDL and who each had a mutation in the SCARB1 gene. They were investigated for their coronary heart disease risk, based on the amount of plaque build up in the arteries of their hearts, and were found to have an 80 percent increased risk of the condition. A similar observation had been made in mice with mutations in the same gene 20 years ago.

The researchers also generated induced pluripotent stem cells from a SCARB1-deficient person and used them to create liver cells. These cells had a profound reduction in their ability to take up HDL. The mutation appeared to stop the SCARB1 receptor from getting to the cell surface where it would normally bind with HDL, explained Professor Daniel Rader, chair of the department of genetics at the University of Pennsylvania in Philadelphia.

Professor Peter Weissberg, medical director at the British Heart Foundation, who was not involved in the study, told BBC News: 'This is an important study that sheds light on one of the major puzzles relating to cholesterol and heart disease. These new findings suggest that the way in which HDL is handled by the body is more important in determining risk of a heart attack than the levels of HDL in the blood.'

Dr Rader concluded: 'Eventually we may want to perform genetic testing in persons with high HDL to make sure they don't have mutations like this one that raise HDL but don't protect against, or may even increase, risk for heart disease.'

The SCARB1 mutation detected by the researchers was found in people of Ashkenazi Jewish descent, so they suggest that genetic testing in this ethnic group might be particularly important.