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Breaking the Cycle

Metabolic syndrome is one of those hot new diseases. Except, it’s not really a disease at all.

And not really new.

It’s a conglomeration of genetic predispositions to conditions such as heart disease, diabetes and obesity, which have a tendency to cluster together.

No matter what metabolic syndrome actually is, Hooman Allayee, one of the newest members of USC’s Institute for Genetic Medicine, is trying to break the cycle, putting some roadblocks in the seemingly inevitable path between the early symptoms of metabolic syndrome and the life-altering diseases that it spawns.

In particular, Allayee, an assistant professor of preventive medicine in the Keck School of Medicine of USC as well as a geneticist, is focusing on the cardiovascular disease component of metabolic syndrome.

In fact, as a postdoc at UCLA, he set out on an ambitious journey to find the human genes responsible for heart disease in humans. But he hadn’t gone far before he began to realize just how ambitious it was.

“It’s difficult to work with human genetics because you can only work with what you get,” Allayee said.

You have to wait and hope for the right kinds of families to come your way and lead you to the root of an already complex disease, said Allayee.

That, he Allayee said, could easily take a decade.

Knowing that, Allayee, in collaboration with UCLA’s Margaret Mehrabian and Jake Lusis, decided to start looking at mice -strains of mice that have naturally occurring genetic variations that make them differ in their susceptibility to disease, no matter what the environment.

“It’s like being on the 405 in bumper-to-bumper traffic,” Allayee said . “That traffic is human genetics. Working with mice is like moving into the carpool lane.”

Once on the fast track, he and his colleagues had a breakthrough – when mice were missing a specific gene called 5-lipoxygenase (or 5-LO), they found, the mice were almost completely protected from heart disease.

This, Allayee said, was an exciting finding.

“We’ve known for a long time that 5-LO is involved in asthma, that it’s an inflammatory gene that promotes inflammation in the lungs. Presumably, it also promotes inflammation in the coronary artery, leading to heart disease.”

Allayee and his team then began collaborating with James Dwyer, professor of preventive medicine in the Keck School, to try and figure out whether this gene also plays a role in human heart disease.

“Dr. Dwyer’s cohort [the Los Angeles Atherosclerosis Study, which follows the cardiovascular health of 470 utility workers in Southern California] had already had their carotid intima media thickness measured – a measure that correlates with blockage in the coronary arteries. And so we were able to look at the variations in the human 5-LO gene to see how they related to artery thickness,” Allayee said.

The results of the study were published in a recent issue of the New England Journal of Medicine.

“We found that people with ‘shorter’ versions of the 5-LO gene had greater intima media thickness – about an 80-micron difference,” he said. “Even after adjusting for cholesterol levels and hypertension and other factors, there was still about a 50-micron difference between those with the short gene and those with the longer version.”

Considering that the average person’s intima media thickens by about 10 microns per year, that means that people with the short gene – in this study at least – are at least five years further along the road to heart disease than their peers, even after lifestyle choices are taken into account.

Now that he’s joined USC and the IGM, Allayee said he plans to follow up on his work. For one thing, he wants to explore the connection between this gene in atherosclerosis and in asthma.

That, he said, may have huge implications.

“There are already 5-LO pathway inhibitors on the market for the treatment of asthma – things like Singulair and Accolade,” he explained. If he can show that these drugs can also affect the development of heart disease, then “pharmaceutical drug companies will be on this.”

That study already is underway, in collaboration with asthma researchers in Florida, and his colleagues at UCLA.

Breaking the Cycle

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