Genome Studies Point to Cholesterol-Regulating
WEDNESDAY, Aug. 4 (HealthDay News) -- Researchers have
identified almost 100 genes in the human genome that may regulate
cholesterol levels and the risk of coronary artery disease,
according to a new study.
Reporting in the Aug. 5 issue of
Nature, the authors suggest that studying these regions may illuminate the genetic basis of cholesterol levels in humans, but they caution that potential clinical applications are many years away.
"There's convincing evidence that at least some of these will be useful on a clinical level," said study co-author Dr. Sekar Kathiresan of Harvard Medical School, although exactly how most of them might regulate cholesterol metabolism remains an open question, he said.
Levels of two kinds of lipids -- cholesterol and triglycerides
-- are known risk factors for heart disease, and about half of the
variability in lipid levels is thought to result from genetic
factors, said Kathiresan.
He and his colleagues measured lipid levels in more than 100,000
people and then scanned their genomes for genetic differences. They
found 95 sites at which tiny differences in genetic sequence seemed
to correlate consistently with differences in lipid levels.
Together, an individual's genetic makeup at these 95 sites seems to
explain about one-quarter of the genetic component of blood lipid
levels, Kathiresan said.
Although the initial analysis was done in people of European
descent, the researchers also performed their analyses on people of
other ethnic backgrounds and found that most of the 95 regions
appear to be important in individuals of African and Asian heritage
About one-third of these sites were already known or suspected
to be important for lipid metabolism; the other two-thirds had not
been tied to lipid levels or coronary artery disease.
"We have now a long list of genes that are relevant in people, and we think it's time to start trying to understand each of those," Kathiresan said. "We think that some of these will in time turn out to be useful drug targets."
As a first step in understanding the biological mechanism
through which one of these genes regulates lipid levels, the
authors then conducted an in-depth analysis of one of the 95 sites.
They found that the gene that had the strongest relationship to
lipid levels was not actually part of the genome that codes for
proteins. Instead, this "non-coding" gene is involved in regulating
the expression of a different gene that directly influences lipid
None of this mechanism was known before to be important in
cholesterol metabolism, Kathiresan said. It's an "entirely new
player in the lipid field."
Similar in-depth analysis of the other 94 sites may uncover
other novel lipid regulators, Kathiresan said. "With that kind of
effort, we think we'll be able to learn a lot about what is
important for lipids in people," he said.
Dr. John LaRosa, of the State University of New York Downstate
Medical Center in Brooklyn, cautioned that it may not be
straightforward to tease apart how these genes influence lipid
levels or risk of coronary artery disease. While a few of them may
regulate lipid metabolism in a simple way, it's likely that many
interact in extremely complex ways, which may be too much for even
powerful computers to resolve, he said.
Some may be important only when triggered by an environmental
factor, and others may simply be false positives that don't
actually contribute to lipid metabolism, LaRosa added.
Still, the work is "great science," LaRosa said, and sets
important groundwork for the future.
What does this mean for the average guy on the street?
"Probably not much," he said, "but they are important studies to do. They build up a database that we need in order to be able to dissect how the genome influences something as remote from the individual gene sites as having high cholesterol."
There's much more on cholesterol at the
American Heart Association.
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