Could be targets for drug treatment, researchers note
MONDAY, Dec. 8 (HealthDay News) -- An international research team that screened the genes of more than 40,000 people has identified 11 more regions that govern levels of blood fats such as LDL cholesterol and triglycerides.
"These locations point us to previously unsuspected players in the metabolism of cholesterol in humans," said Dr. Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital, and lead author of a report in the Dec. 7 online issue of Nature Genetics. "Now that we have these additional genes that play a role in humans, we have to figure out how they do it by doing additional studies."
The report brings the total number of genes associated with control of blood fat levels to 30. One of those 30 is a gene designated HMGCR, which is the target of the widely used statins.
"By further understanding how these new genes play their roles, some of the genes could become targets themselves and help reduce cholesterol levels and heart disease," Kathiresan said.
The researchers, based at 37 institutions in the United States and around the world, started with genetic information on participants in the Framingham Heart Study, which first established the role of LDL cholesterol in cardiovascular disease in 1961. They added genetic samples from another 20,600 participants in five different studies.
"Of the three billion letters in the human genome, 2.5 million spots differ between people," Kathiresan said. "We tried to correlate blood levels of LDL cholesterol, HDL cholesterol and triglycerides."
Some of the 11 newly identified genes are known to have rare mutations that cause serious cholesterol disorders or conditions such as type 2 diabetes. This study shows for the first time that common variations in the genes are associated with differing lipid levels in individuals.
Putting together the information from the different studies was a challenge, said Goncalo Abecasis, an associate professor of biostatistics at the University of Michigan, and a member of the research team. He and his colleagues at the university's Center for Statistical Genetics helped develop the computer software that made the analysis possible.
While all the studies looked at the same genes, they did not always look for the same variants of those genes, Abecasis said. "So, we had to ask, are they really telling us something consistent? The method we used was that, we can find different little stretches of DNA that are shared between people and find relationships between those stretches."
The information has several possible applications, Kathiresan said. "We might use this genetic information to identify people at an earlier age, in their 30s or 40s, who are destined to develop high cholesterol levels and eventually heart disease," he said.
New light will also be shed on the metabolism of blood fats such as LDL cholesterol, the "bad" kind that forms artery-blocking plaques, Kathiresan said. And aside from basic biological knowledge, the discovery could lead to new drug treatments to prevent artery blockage.
"Time will tell whether any of the 11 new locations will end up being as good a drug target as HMGCR," he said.
The 30 genes that have so far been identified are believed to account for about 20 percent of the variations in individual blood levels of cholesterol and other fats. Even larger studies of people in different ethnic groups are needed to find other genetic factors, and their overall contribution to cardiovascular risk.
"We are currently designing studies to test whether individuals inheriting several of these lipid risk genes really are at higher risk for heart attack and whether they are more likely to benefit from cholesterol-lowering treatments like statins," Kathiresan said.
The role of cholesterol in the cardiovascular system is explained by the U.S. National Heart, Lung, and Blood Institute.
SOURCES: Sekar Kathiresan, M.D., director, preventive cardiology, Massachusetts General Hospital, Boston; Goncalo Abecasis, Ph.D., associate professor, biostatistics, University of Michigan, Ann Arbor; Dec. 7, 2008, Nature Genetics, online
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