The study – published in The Lancet – challenges the assumption that raising levels of ‘good high-density lipoprotein (HDL) cholesterol will necessarily lower the risk of heart disease.
"It's been assumed that if a patient, or group of patients, did something to cause their HDL levels to go up, then you can safely assume that their risk of heart attack will go down," said senior author Sekar Kathiresan, an associate professor of medicine at Harvard Medical School. "This work fundamentally questions that."
The international team, led by researchers at the Broad Institute and Massachusetts General Hospital, USA, explored naturally occurring genetic variations in humans to test the connection between HDL levels and heart attack. By studying the genes of nearly 170,000 individuals, the team discovered that, when examined together, the 15 HDL-raising variants they tested do not reduce the risk of heart attack.
"Our study highlights the value of human genetic information in understanding disease biology,” said Professor David Altshuler of the Broad Institute and Harvard Medical School, who co-authored the study.
"This kind of research is not about personalised prediction — rather, it's about testing mechanisms and therapeutic hypotheses," he said.
The researchers said their findings raise significant questions over whether products that are aimed at raising levels of HDL-cholesterol will prove effective in lowering heart attack risk across the population.
Cholesterol and heart health
There is a well-studied connection between elevated LDL - often called 'bad cholesterol' - and heart attack. Decades of research have since shown beyond any reasonable doubt that many different methods of reducing a person's LDL levels lower the risk of heart disease. However, it has been difficult for researchers to prove conclusively that raising HDL levels is beneficial.
"We know that HDL is a great biomarker — it's quite useful in identifying individuals at higher risk of having a heart attack in the future," said Kathiresan. "But we have shown that you cannot assume that raising HDL by any mechanism will help patients. Perhaps other mechanisms exist that can lower risk, but we will need to keep searching for them."
The researchers explained that individuals typically carry two copies of each gene in the genome – which copy a child will inherit from each parent is essentially a random decision.
This phenomenon, sometimes called ‘Mendelian randomization’, provides a powerful means of testing connections between genes, biomarkers, and disease, says the researchers.
Using this technique, Kathiresan and his team tested whether certain genetic variants that can raise HDL levels impact the chances of developing heart attack – what they found was surprising, they claim.
Individuals who carried a particular variation in a gene for endothelial lipase had HDL levels that were elevated about 6mg/dl (around a 10% increased level). Such a change is expected to decrease heart attack risk by about 13%, however, the individuals showed no difference in their risk of heart disease compared to people without the variant.
The researchers devised a scoring system based on the total number of copies of the gene variants a person carries — ranging from 0 to 28 — and then asked whether that score relates to the risk of heart attack. They found no association for any.
Source: The Lancet
Published online ahead of print, doi: 10.1016/S0140-6736
“Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study”
Authors: Benjamin F Voight, Gina M Peloso, Marju Orho-Melander, Ruth Frikke-Schmidt et al