cholesterol

Getting to the Heart of the Matter

Why do some patients with high ‘good’ cholesterol also show signs of heart disease? UConn research has found the common gene mutation that may be to blame.

By Kim Krieger

Scientific image of kidney cells dyed colors to show mutated cells

UConn Health endocrinologist Dr. Annabelle Rodriguez-Oquendo’s lab used color stains to figure out where the kidney cells were expressing a mutant gene: those areas glow yellow in this picture. Most of the yellow is in the endoplasmic reticulum, the cell’s transportation network. Photograph provided by Annabelle Rodriquez-Oquendo


Guidelines about cholesterol used to be straightforward: high-density lipoprotein (HDL) cholesterol is healthy, and low-density lipoprotein (LDL) cholesterol is not. Relatively high levels of HDL were no cause for concern, as long as LDL was low.

But recent discoveries show that may be an oversimplification. A common variant in a gene that regulates cholesterol levels may raise the risk of heart disease in carriers with high HDL, according to a new UConn Health study.

Researchers examined a variant called missense rs4238001, which alters the type of protein made by the gene SCARB1. The variant form of SCARB1 changes a liver receptor protein from a glycine to a serine. The change occurs in the liver receptor that grabs HDL out of the blood and breaks it down for disposal. The variant protein makes the receptor more fragile and not as effective at latching onto HDL, leading to higher levels of HDL in the bloodstream.

The study, led by Dr. Annabelle Rodriguez-Oquendo, an endocrinologist at UConn Health, was based on information about more than 5,000 people who participated in the Multi-Ethnic Study of Atherosclerosis in major American cities from 2000 to 2002.

The risk of heart disease among those with the variant was up to 49 percent greater than in the general population.

Rodriguez-Oquendo and her colleagues charted the genotypes of the participants and tracked episodes of heart disease over a period of seven years.

They found that the variant was associated with an increased risk of heart disease, particularly among men and African Americans, findings that were published in the May 20 issue of PLOS ONE.

The risk of heart disease among participants with the rs4238001 variant was up to 49 percent greater than the risk in the general population. Overall, men with the variant had a 29 percent higher risk of heart disease than men without it. African American males with the variant fared the worst, with a 49 percent increased risk. For white males with the variant, the risk was 24 percent higher.

The gene mutation itself is not rare, according to Rodriguez-Oquendo. It occurs in less than 3 percent of Chinese Americans, about 8 percent of African Americans, and 10 to 12 percent of Latinos and Caucasians in the U.S. A genetic test for the rs4238001 variant is already available to help clinicians identify patients who are carriers, so that they can offer counseling about heart risk prevention.

Dr. Annabelle Rodriguez- Oquendo and team

UConn Health endocrinologist Dr. Annabelle Rodriguez-Oquendo looks at DNA data with researchers in her lab. Peter Morenus – UConn Photo

UConn Health endocrinologist Dr. Carl Malchoff uses the test to help patients who aren’t sure whether or how they should treat their high cholesterol. For example, Malchoff had one patient with high HDL and a family history of longevity. But she had suffered a stroke at a young age, and wanted more information before deciding on a treatment.

This particular patient tested negative for the variant. But those who test positive would be advised to use a more aggressive type and dose of cholesterol medication. Patients with the variant could also inform their children that they might also have it.

“Usually if patients don’t have the variant, we assume their high HDL is protective,” Malchoff says.

Sometimes, however, a treatment decision might be more ambiguous, and could require further information before the best therapy is chosen. Another patient of Malchoff’s had high levels of both HDL and LDL cholesterol. She was taking a statin to lower her cholesterol, but was experiencing terrible muscle pain as a side effect. She wondered if there was a way to tell whether her high HDL protected her from the heart disease risk associated with high LDL. If so, could she stop taking the statin?

This patient could be tested for the same variant. If her test was negative, she could assume that her high HDL cholesterol was helping protect her against heart attack, even with high levels of LDL cholesterol. If the test was positive, she would know that her high HDL cholesterol would not protect her. She could then take another type of cholesterol-lowering medication, just not one classified as a statin.

Malchoff and his colleagues at UConn Health are working with Rodriguez-Oquendo to determine when testing for the variant is most helpful.

Read the full research article at the PLOS ONE website.

“My approach to patient care in an academic center is that we should look for things our colleagues in practice can’t do and do those things, so we can help them and be their partners,” Malchoff says of his role in the research.

Now that the UConn study has made the connection between the mutation in SCARB1 and heart disease, the researchers want to figure out a way to fix it.

“We want to go deep in the cell, and figure out how to repair it,” Rodriguez-Oquendo says. The researchers don’t know exactly why changing the protein in a liver receptor from a glycine to a serine makes it more fragile. “We’re really interested in understanding more about how this protein gets chewed up and degraded faster.”

The answers may impact the current standard of care for heart disease prevention and treatment for patients who are carriers of this genetic variant. That could happen through indirect means, such as adjusting hormone levels to alter cholesterol metabolism, or in the future through direct means such as genetic therapy.