Rare Mutation Increases Both HDL-Cholesterol and Heart Disease Risk

Increased risk of atherosclerosis has been attributed to a rare mutation in the gene that encodes the major liver cell receptor for HDL (high-density lipoprotein).

Scavenger receptor class B, type I (SR-BI), which is encoded by the SCARB1 gene, is an integral membrane protein found in numerous cell types, including those in the liver and adrenal glands. It is best known for its role in facilitating the uptake of cholesteryl-esters from HDL in the liver. This process drives the movement of cholesterol from peripheral tissues towards the liver for excretion and is a protective mechanism against the development of atherosclerosis.


Cardiovascular disease investigators at the University of Pennsylvania (Philadelphia, USA) focused on SCARB1 after finding that mice with depleted SCARB1 (SR-BI knockout mice) had markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and coronary heart disease risk in humans was not clear.

To clarify the link between SCARB1 and HDL-C levels the investigators conducted targeted DNA sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels. As a consequence, they identified a homozygote for a loss-of-function variant, in which leucine replaced proline 376 (P376L), in SCARB1. The mutant gene coded for a nonfunctional form of the SR-BI receptor.

The investigators reported in the March 11, 2016, issue of the journal Science that inactive SR-BI blocked HDL-C uptake by liver cells from an individual with two copies of the mutant SCARB1 gene, in induced pluripotent stem cells derived from this individual and converted into liver cells, and in SCARB1 knockout mice. In addition, large population-based studies revealed that subjects who were heterozygous carriers of the P376L variant had significantly increased levels of plasma HDL-C but also an increased risk of coronary heart disease.

“This mutation prevents the receptor from getting to the cell surface where it needs to be situated in order to bind and take up HDL,” said senior author Dr. Daniel J. Rader, professor of genetics at the University of Pennsylvania. “This disruption in the receptor’s job is due to mistakes in its folding and processing during protein synthesis. Our results indicate that some causes of raised HDL actually increase risk for heart disease. This is the first demonstration of a genetic mutation that raises HDL but increases risk of heart disease.”

“The work demonstrates that the protective effects of HDL are more dependent upon how it functions than merely how much of it is present,” said Dr. Rader. “We still have a lot to learn about the relationship between HDL function and heart disease risk. Our results indicate that some causes of raised HDL actually increase risk for heart disease. Eventually we may want to perform genetic testing in persons with high HDL to make sure they do not have mutations—like this one—that raise HDL but does not protect against, or may even increase, risk for heart disease.”

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