When HDL cholesterol doesn’t protect against heart disease

At a Glance Scientists discovered a genetic mutation that raises HDL cholesterol levels but, rather than protecting against heart disease, increases the risk for it.

The findings suggest that levels of HDL cholesterol may not be as important as how well it functions to remove cholesterol from the body.

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Cholesterol has many important functions. It’s carried through the blood stream in several forms, including attached to low-density lipoproteins (LDL) and high-density lipoproteins (HDL). When there’s too much cholesterol in your blood, the LDL-cholesterol can combine with other substances to form plaque that coats artery walls, causing them to narrow. This condition, called atherosclerosis, increases your risk for cardiovascular diseases such as heart attack and stroke.

HDL, in contrast, is thought to remove cholesterol from arteries and carry it to the liver for removal from the body. Higher levels of HDL have been associated with a lower risk of cardiovascular disease. However, pharmaceutical approaches to reduce heart disease risk by raising HDL levels have had disappointing results.

An international research team led by Dr. Daniel J. Rader at the University of Pennsylvania aimed to gain further insights into the relationship between HDL-cholesterol (HDL-C) and cardiovascular disease. They examined 328 people with very high HDL-C (average of 107 mg/dl) and 398 with low HDL-C (average of 30 mg/dl). The scientists sequenced nearly a thousand genes near genetic regions previously associated with plasma lipid levels. Their work was funded in part by NIH’s National Center for Research Resources (NCRR) and National Center for Advancing Translational Sciences (NCATS). Results appeared on March 11, 2016 in Science.

In 5 people with high HDL-C, the researchers found a genetic variant within the gene SCARB1, which codes for the major HDL receptor on liver cells, scavenger receptor class BI (SR-BI). One of the individuals had 2 mutant copies of the variant. In mice, genetic manipulations of this gene had effects opposite from those expected if HDL-C were protective. Overexpression of the gene lowered HDL-C levels but reduced atherosclerosis. Deletion raised HDL-C levels but increased atherosclerosis.

Genetic analyses of well over 300,000 people confirmed that the variant, called SCARB1 P376L, was associated with elevated HDL-C levels. The researchers found that people with the variant had unusually high levels of large HDL-C particles in their blood.

To see whether SCARB1 P376L was associated with heart disease, the team acquired data from nearly 50,000 people with coronary heart disease and about 88,000 controls. They found that those with the variant had a significantly higher risk of heart disease.

Experiments in cell cultures and mice revealed that the P376L SR-BI protein wasn’t processed properly by the cell and often failed to reach the cell surface. As a result, liver cells became incapable of taking up HDL cholesterol from the blood.

“The work demonstrates that the protective effects of HDL are more dependent upon how it functions than merely how much of it is present,” Rader says. “We still have a lot to learn about the relationship between HDL function and heart disease risk.”

The team plans to study how other SCARB1 mutations affect HDL levels and heart disease. Other genes, they suggest, may also have similar effects.

—by Harrison Wein, Ph.D.