HDL, the good cholesterol, may not be so good after all
by Thomas H. Maugh II
A new genetic study suggests that high-density lipoprotein, the so-called good cholesterol commonly known as HDL, may not actually be as good for us as physicians previously thought. A study of more than 100,000 people found that those with genes that promote production of higher-than-normal levels of HDL do not have a lower risk of having a heart attack, a finding that has surprised researchers immensely.
The results could have major implications for pharmaceutical manufacturers, who have been attempting to develop drugs that will raise HDL in the hopes of preventing heart attacks in people at higher risk.
Lipoproteins in the blood come in two forms, high- and low-density or LDL. Epidemiological studies have shown that elevated levels of LDL are strongly associated with an increased risk of heart attack, and drugs that lower LDL have been shown definitively to reduce that risk. The most commonly used drugs are the family of agents known as statins, which are now one of the most widely prescribed medications in the world. Similar epidemiological studies have shown that above-normal levels of HDL are associated with a decreased risk of heart attack. But because there are no drugs that raise HDL, researchers have been unable to prove that the high HDL levels are the cause of the reduced risk.
A team headed by Dr. Sekar Kathiresan of Harvard Medical School thus turned to genetics to seek a better understanding of the role of HDL, using a technique called Mendelian randomization, in which they compared people carrying a specific gene with those who do not carry it. They first looked at subjects with a mutant form of a gene for a protein called endothelial lipase; people with the variant have HDL levels that are about 10% above normal, a level that — according to conventional wisdom — should reduce the risk of heart attack by about 13%. The team reported in the journal Lancet, however, that individuals with the variant had the same risk of heart attack as people without it.
They then looked at a suite of 14 genes, each of which is thought to increase levels of HDL. Again, those with any of the genes had no reduced level of risk. Significantly, when the team performed a similar analysis of genes that increase levels of LDL, they found an increased risk of heart attacks.
Based on the studies, the authors concluded that “Interventions (lifestyle or pharmacological) that raise plasma HDL levels cannot be assumed ipso facto to lead to a corresponding benefit with respect to risk of myocardial infarction [heart attack].”
Researchers speculate that the epidemiological link between higher HDL and lower heart attack risk may be caused by some other, as-yet-unknown factor that both lowers heart attack risk and increases HDL levels.