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Elevated levels of HDL caused by gene mutation may increase CHD risk
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In a study published in Science, an international team of scientists, including researchers from the Perelman School of Medicine at the University of Pennsylvania, suggest that a genetic mutation that raises HDL may increase risk for CHD.
“The thinking about HDL has evolved recently to the concept that it may not directly protect against all heart diseases,” Daniel J. Rader, MD, chair of the department of genetics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, said in a press release. “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.”
Daniel J. Rader
A rare, but significant mutation
The researchers compared the genetic sequencing of 328 people with elevated HDL (mean HDL, 106.8 mg/dL) with the sequencing of a control group of 398 participants with lower HDL (mean HDL, 30.4 mg/dL) and identified one participant (a homozygote) in the high HDL group who had two copies of a loss-of-function variant called P376L in SCARB1, a gene which encodes for scavenger receptor BI (SR-BI). Four heterozygotes in the high HDL group also had the P376L mutation, but only one copy each. P376L was not found in any of the participants in the low HDL group (P = .008, Fisher’s exact test).
The researchers then expanded their study to include another 524 participants with high HDL (mean HDL, 95 mg/dL) and 758 participants with low HDL (mean HDL, 33.5 mg/dL), and they found another 11 heterozygotes for P376L in the high HDL group and three in the low HDL group (minor allele frequency = 0.01 in high HDL vs. 0.0013 in low HDL; P = .000127, Fisher’s exact test), indicating that it was more prevalent in those with high HDL.
A further expansion to include more than 300,000 individuals from the Global Lipid Genetics Consortium confirmed that the P376L variant was only associated with elevated HDL levels with a large effect size (beta = 8.4 mg/dL; P = 1.4 x 10-15)
Next, the one homozygote and eight of the heterozygotes and all noncarriers in both the high and low HDL groups all underwent further phenotyping. The researchers found that both the homozygote and the heterozygotes had increased cholesterol and apolipoprotein A-I levels in HDL compared with those without the variant, but that the HDL ApoA-II levels were not at abnormal levels. Compared with the controls, the heterozygote had a more than double increase in large HDL-2b particles. The increase for the homozygote was more than six times that of the controls.
To better understand how the mutation effected SR-BI function, the researchers created liver cells using pluripotent stem cells from the homozygote and a noncarrier.
“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,” Rader said in the release. “This disruption in the receptor’s job is due to mistakes in its folding and processing during protein synthesis.”
Higher HDL not always good
Further studies on mice and humans confirmed that the overexpression of SR-BI reduced HDL levels and atherosclerosis while the overexpression of the P376L variant led to higher levels of HDL and accelerated atherosclerosis. A meta-analysis of human participants from the CARDIoGRAM Exome Consortium and the CHD Exome+ Consortium showed that the CHD risk for P376L carriers was higher than noncarriers (OR for disease among carriers = 1.79; P = .018).
The University of Pennsylvania team plans to investigate whether the same effects can be seen in other SCARB1 mutations, according to the press release.
“Eventually we may want to perform genetic testing in persons with high HDL to make sure they don’t have mutations — like this one — that raise HDL, but don’t protect against, or may even increase risk for heart disease,” Rader said.
One possible treatment for this genetically elevated HDL is to improve the functioning of the SCARB1, but whether lowering HDL will decrease or increase heart disease risk is still unknown.
“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 concluded. “We still have a lot to learn about the relationship between HDL function and heart disease risk.” – by Tracey Romero
Disclosure: Rader reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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