In today’s New England Journal of Medicine, a large team of geneticists unveil evidence for a genetic polymorphism that increases the risk for cardiovascular disease in as many as 1 out of 6 people. That’s pretty big news. But the culprit identified in their genome-wide assay is not a new character on the cardiology scene: Lp(a) lipoprotein, an unusual particle that has been known in the field for nearly 50 years.
It just so happens that we have one of the world’s foremost experts on Lp(a) here at the University of Chicago Medical Center in Angelo Scanu, a professor of cardiology who has been with the hospital since 1961. Scanu, who also is known for biochemically characterizing the “good cholesterol” HDL, was the first to publish in 1987 that the structure of Lp(a) resembles plasminogen, an agent involved in breaking up blood clots. That finding suggested that Lp(a), discovered in 1963 by Norwegian researcher Kåre Berg, could somehow interfere with the removal of clots, an effect that might lead to blockage and heart attacks.
“We discovered something that overnight, made the field just go, “Boom,” Scanu said. “It brought cardiology together with the field of thrombosis.”
But while studies repeatedly showed that Lp(a) was associated with an increased risk for cardiovascular disease, researchers could not determine whether high Lp(a) levels were the cause of the disease or the result. That mystery was due in part to several struggles, including:
- Lp(a) blood levels vary widely between different ethnic groups, varying by almost 1000 times among individuals. Further, average Lp(a) levels are much higher in people of South Asian or African origin than people of European descent.
- Lp(a) is only found in humans and some non-human primates, making animal research nearly impossible.
- No drug has been shown to effectively reduce Lp(a) levels, save niacin, which can only do so at doses that cause serious side effects. Drugs commonly prescribed to lower cholesterol such as statins have no effect on Lp(a) levels.
- Despite decades of studies showing an association with cardiovascular disease, nobody is really sure what Lp(a) actually does!
Hence Scanu’s diagnosis of Lp(a), a particle he has spent three decades studying, as “a miserable snake,” a mysterious and frustrating particle.
The new study, which looked at genetic polymorphisms in more than 3000 Europeans with coronary artery disease compared to 3000 controls, found several polymorphisms of the gene that makes Lp(a) were significantly associated with an elevated risk for the disease. Two gene variants in particular raised a person’s risk of heart attack nearly fivefold, if they were so unlucky to have both variants at once. Because these genetic variants also caused high levels of circulating Lp(a), the authors concluded that the result was “consistent with a causal role of an increased Lp(a) lipoprotein level in coronary disease.”
But Scanu, though he has long argued that Lp(a) is a very important factor and describes the new paper as “a remarkable study,” remains unconvinced that this is the end of the mystery.
“You can study genes up to a point, and the gene can control synthesis of the protein. But the environment plays an important role in modifying that gene product. The issue here is that you must study also the protein,” Scanu said. “We need to do more structure so we can define exactly why does Lp(a) cause a problem.”
The greater impact of the new genetic study, Scanu reasoned, may be to put Lp(a) back in the spotlight, raising the profile of the particle after two decades of research frustration placed it out of favor in some clinics. But Scanu, who recently retired as director of the University of Chicago Lipid Clinic, said that the results would have done little to change his clinical approach, which involves testing patients for Lp(a) levels. The genetic basis of Lp(a) has long been known, he said – when a patient was found to have high Lp(a) levels, Scanu recommends that their entire family be tested.
But because no direct intervention has been found to change Lp(a) blood levels, Scanu’s philosophy with such patients is to “go around the iceberg.”
“My message is this: you have a bad gene, let’s find out if it’s in your family, and for yourself let us correct what is correctable,” Scanu said. That includes living a healthier lifestyle, and treating other conditions such as diabetes, hypertension and obesity. There’s an added motivation to successfully minimize the risks of cardiovascular disease; after the age of 66, for reasons that are similarly mysterous, there’s evidence that Lp(a) reverses to being protective against heart disease, Scanu said.
Aside from clinical impact, Scanu said he hopes that the NEJM paper will excite people again about Lp(a) research, which he continues in his own laboratory.
“It used to be Lp(a) all over the place, then suddenly the field is dormant, so we hope this genome-wide study will maybe raise the issue again,” Scanu said. “If you find out how it works, it will be great. We should put money into fundamental research, basic research. The structure work needs to be done and we hope to stick with this for a while.”