The idea is that people inherit any of a wide variety of genetic variations that determine how much HDL they produce. The result is that people are naturally and randomly assigned by these variations in their inherited genes to make more, or less, HDL, throughout their lives. If HDL reduces the risk of heart disease, then those who make more should be at lower risk.

For purposes of comparison, the researchers also examined inherited variations in 13 genes that determine levels of LDL, the so-called bad cholesterol. It is well known and widely accepted that lowering LDL levels by any means — diet and exercise, statin drugs — reduces risk. Clinical trials with statins established with certainty that reducing LDL levels is protective. So, the researchers asked, did people who inherited gene variations that affected their LDL levels, have correspondingly higher or lower heart disease risk?

The study found, as expected, that gene variations that raise LDL increase risk and those that lower LDL decrease risk. The gene effects often were tiny, altering LDL levels by only a few percent. But the data, involving tens of thousands of people, clearly showed effects on risk.

“That speaks to how powerful LDL is,” Dr. Kathiresan said.

But the HDL story was very different. First the investigators looked at variations in a well-known gene, endothelial lipase, that affects only HDL. About 2.6 percent of the population has a variation in that gene that raises their HDL levels by about 6 points. The investigators looked at 116,000 people, asking if they had the variant and if those who carried the HDL-raising variant had lower risk for heart disease.

“We found absolutely no association between the HDL-boosting variant and risk for heart disease,” Dr. Kathiresan said. “That was very surprising to us.”

Then they looked at a group of 14 gene variants that also affect HDL levels, asking if there was a relationship between these variants and risk for heart disease. The data included genetic data on 53,500 people. Once again, there was no association between having the variants that increased HDL and risk of heart disease.

Dr. Lauer explains what that means with an analogy.

“One might think of a highway accident that causes a massive traffic jam,” he said. “Stewing in the jam many miles away, I might be tempted to strike the sign that says ‘accident ahead,’ but that won’t do any good. The ‘accident-ahead’ sign is not the cause of the traffic jam — the accident is. Analogously, targeting HDL won’t help if it’s merely a sign.”