March 10, 2016

expert reaction to study investigating levels of ‘good’ cholesterol and heart disease risk in people with a rare genetic variant

A study published in the journal Science reported the discovery of a rare genetic variant associated with high levels of HDL cholesterol (HDL-C), normally termed ‘good cholesterol’, and also associated with an increased risk of heart disease.

Dr. Tim Chico, Reader in Cardiovascular Medicine / consultant cardiologist, University of Sheffield, said:

“Most people have come across idea that there is “good” cholesterol (HDL) and “bad” cholesterol (LDL) but this important study adds to other results showing it isn’t as simple as good and bad. Although some people with naturally high HDL appear to have a lower chance of heart attack, this doesn’t mean that the high HDL level is the cause of the reduced risk.

“We now know that it is possible to have a higher HDL level due to genetic differences and either not have a lower risk of heart disease (as seen in previous studies) or in the case of this new study, actually be at higher risk of disease, depending on the genes affected.

“Although there are drugs that can increase HDL levels, these do not reduce the risk of heart disease. These drugs are niacin, which is rarely used, and CETP inhibitors which have only been used in experimental studies and are not used in routine practice. Statins reduced LDL (“bad” cholesterol), and are clearly beneficial in people with existing or high risk of heart disease. The current study does not alter any of the recommendations for who should receive treatment with statins or other drugs.

“It is worth noting that exercise both increases HDL and reduces the risk of heart disease. These results suggest that the beneficial effect of exercise is probably not caused by higher HDL levels, although more research is needed to fully understand the complex relationship between HDL and risk of heart disease.”

Dr. Michael Holmes, Senior Clinical Research Fellow in Cardiovascular Medicine, Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), University of Oxford, said:

“The authors have conducted a sophisticated analysis to identify a loss of function genetic variant in a gene called SCARB1 that results in an increased concentration of high density lipoprotein-cholesterol (HDL-C; usually termed “good” cholesterol, as observational studies typically show an inverse association between HDL-C levels and risk of coronary heart disease). Unexpectedly, the authors show that while the genetic variant increases HDL-C, it also increases risk of coronary heart disease.

“HDL is involved in moving cholesterol from peripheral tissues to the liver, where the cholesterol is metabolised and excreted. So, HDL is responsible for clearing cholesterol from the arteries among other places. In order for this to happen, the cholesterol carried by HDL needs to be transported to liver cells through binding with a receptor called scavenger receptor BI (SR-BI), which is coded for by the SCARB1 gene. If this receptor no longer functions (e.g. with a genetic variant that causes loss of function of the receptor), then HDL-C levels in the blood increase. This increase in HDL-C levels does not reflect an increase in clearing of cholesterol from the peripheral tissues, but rather, reflects impaired binding of HDL-C to its receptor in the liver, and impaired clearance of HDL-C from the blood. This results in reduced clearance of peripheral cholesterol through reverse cholesterol transport, increased furring of arteries (atherosclerosis) and an increase in risk of coronary heart disease.

“The findings that the authors present are interesting, not because they suggest higher levels of “good” cholesterol increase the risk of coronary heart disease, but rather because they present genetic evidence that “good” cholesterol plays a causal, protective, role in reducing the risk of coronary heart disease. Here we have the blockade of an HDL-C receptor that impairs the normal function of HDL-C to clear cholesterol from the peripheral tissue. This blockade is associated with an increased risk of heart disease. The logical interpretation is that the normal function of good cholesterol (HDL-C), to transport cholesterol from the tissue to the liver, results in a reduction in risk of heart disease.

“The take home message is that an increase in HDL-C due to increased peripheral cholesterol clearance could reduce the risk of coronary heart disease, whereas an increase in HDL-C due to reduced clearance of cholesterol to the liver (as occurs with this genetic variant) is likely to be associated with an increased risk of coronary heart disease. Importantly, both scenarios are consistent with a protective role of HDL-C in reducing the risk of coronary heart disease by means of reverse transport of cholesterol. The key challenge now is how to translate this knowledge into therapies that lower the risk of heart disease.”

Prof. Keith Frayn, Emeritus Professor of Human Metabolism, University of Oxford, said:

“High levels of HDL-cholesterol in the blood are associated, in epidemiological studies, with decreased risk of coronary heart disease (CHD).  It is generally accepted that this reflects the role of HDL-cholesterol in the pathway of reverse cholesterol transport, in which excess cholesterol is transferred from other tissues to the liver, from which it can be excreted.

“There are two types of drug in clinical use that raise HDL-cholesterol levels.  The fibrates act by altering the expression in the liver of the proteins that are involved in HDL production.  Niacin (or nicotinic acid) substantially raises HDL-cholesterol levels but the mechanism is not clear.  Both fibrates and niacin have been shown to reduce the risk of CHD in some studies, although for niacin this has not been borne out in larger studies.  Their clinical value is therefore unclear although both continue to be used.  Recently a new class of drugs raising HDL-cholesterol has been tested: the cholesteryl ester transfer protein (CETP) inhibitors.  These drugs have a substantial effect on HDL cholesterol but several trials have been aborted because of excess deaths or other unwanted effects.

“This illustrates that the interpretation of the blood concentration of HDL-cholesterol is complex.  If the level is high because the reverse cholesterol transport pathway is working well, that is probably good for the heart.  But if the level is high because the pathway is blocked at some point, that clearly would not be good.  The CETP inhibitors probably block part of the pathway by which cholesterol is returned to the liver and this may explain the lack of beneficial effect (and highlights the complexity of the pathway).

“The present paper describes a patient with a mutation in the Scavenger receptor BI (SR-BI), which is one of the receptors believed to be important for transferring cholesterol from HDL into the liver for excretion. Such a mutation would be predicted to raise HDL-cholesterol concentrations, as observed. The authors also show that in a larger group of individuals carrying this mutation, there is an increased risk of CHD, despite their high HDL-cholesterol concentrations. Because cholesterol excretion is presumably reduced by the mutated receptor, this again is fairly predictable. But the findings do help to elucidate the complex pathway of reverse cholesterol transport in humans. The importance of SR-BI is well established in mice, but it was not previously clear just what role it plays in humans. Now we potentially have a new target for drugs to increase cholesterol excretion.

“This is reminiscent of earlier studies of mutations affecting HDL-cholesterol concentrations, particularly the discovery of the gene mutated in Tangier disease, a condition in which HDL-cholesterol concentrations are (in contrast) very low. The gene affected in Tangier disease codes for another protein involved in cholesterol transport, called ABC-A1, in that case involved in moving cholesterol out of cells and into HDL.

“So the study of mutations affecting HDL-cholesterol concentrations is helping us to unravel the mechanisms of cholesterol excretion, and another piece of the jigsaw is now in place. These findings do point again, however, to the difficulty of interpreting blood HDL-cholesterol levels without further information.”

‘Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease’ by Paolo Zanoni et al., published in Science on Thursday 10 March 2016.

Declared interests

Dr. Tim Chico: “I am a committee member and Treasurer of the British Atherosclerosis Society, a charity established in 1999 with the aim of promoting UK atherosclerosis research.”

Dr. Michael Holmes: “I don’t have any conflicts of interest. I have received funding from the UK MRC in the past 5 years as part of a population health scientist fellowship.”

Prof. Keith Frayn: “No conflict of interest to declare.”