A genomic study has identified individuals with a mutation that led to both high levels of high-density lipoprotein (HDL) and an increased risk of heart disease. The findings further call into question the idea that HDL is good for cardiovascular health.

"This study, and other studies, brings that [causal link] very much into question," Daniel Rader told BioWorld Today.

Rader is professor of molecular medicine at the University of Pennsylvania Medical School, and the senior author of the paper reporting the findings, which appeared in the March 11, 2016, issue of Science.

The idea that HDL levels should be high, he said, is based on "quite extensive epidemiology" showing an inverse correlation between HDL levels and cardiovascular disease risk.

Given that HDL removes cholesterol from the circulation, there is a plausible mechanism for how high HDL levels might have beneficial effects.

Epidemiology data are necessarily observational, however, and cannot establish cause and effect. And in the case of HDL, that causal link is proving elusive.

Clinical trials attempting to raise HDL levels have not succeeded in lowering the risk of cardiovascular disease.

Animal studies have shown that under certain circumstances, the relationship between HDL and cardiovascular disease could be the opposite of that predicted by the epidemiology data.

HDL's job is to bind cholesterol and transport it to the liver for uptake via the SR-B1 receptor. Knockout mice that did not have the liver cholesterol receptor SR-B1 had both high levels of cholesterol and more atherosclerotic plaque, while transgenic animals overexpressing the receptor had both lower HDL levels and lower plaque burden.

The reason was that in the absence of the receptor to take the cholesterol in the liver, HDL was up-regulated in a futile attempt to improve cholesterol scavenging, leading to high levels of HDL that were not doing any good because there was nowhere for them to get rid of their cholesterol cargo.

In their study, Rader and his team wanted to see whether in humans, high levels of HDL could also be indicative of a problem with the SR-B1 receptor. To test their idea, they first sequenced relevant exons of roughly 700 individuals whose HDL levels were either quite high or quite low.

In the individuals with high HDL, they identified one subject that had two nonfunctional copies of SR-B1, and four with one nonfunctional copy. The team went on to do a large-scale genotyping analysis and found that individuals with only one functional copy of SR-B1 had both higher HDL levels and an increased risk of heart disease.

For individual patients and drug developers alike, the main lesson from the study is that high HDL levels are not necessarily protective against plaque and cardiovascular disease.

In fact, Rader said he believes that "mostly, HDL is neutral." The epidemiological association of HDL and cardiovascular health comes from the fact that low HDL is a proxy for other things that are bad for the heart, such as a lack of exercise and surfeit of junk food.

Rader's team wants to look at other gene variants in the SCARB1 gene, which codes for the SR-B1 receptor. A more thorough understanding of different mutations will allow a better assessment of whether HDL is a proxy for heart disease risk enough of the time to make it a useful biomarker.

"This study could not really have been done even five years ago," he said – not so much because of the sequencing, which could have been done, albeit more slowly at greater expense. The real progress, he said, has come in the area of the chips that his team used to genotype hundreds of thousands of people, allowing them to pin down the association between the P376L gene variant and cardiovascular disease risk.

Accruing such patient numbers also necessitated large-scale collaboration, which is reflected in the fact that in addition to nearly 50 individual authors, the paper also gives authorship status to no fewer than 10 consortia – the CHD Exome+ Consortium, PROSPER Study Group, Cardiogram Exome Consortium, WOSCOPS Consortium, BRAVE Investigators, Global Lipids Genetics Consortium, Copenhagen Heart Study, PROMIS Investigators, MORGAM Investigators and EPIC-CVD Consortium.

The study also suggests that increasing SR-BI levels in the liver might be therapeutically useful for lowering cardiovascular disease risk.

Rader said such an approach, ironically, "doesn't look so good" according to the current way of assessing the cardiovascular benefit of an intervention, because HDL cholesterol levels would likely decrease in response to such a treatment, as cholesterol uptake became more efficient. "But the mechanism is such that it could be helpful."