The New York Times, By GINA KOLATA, December 11, 2008
For the sake of heart disease research, 809 members of the Old Order Amish community agreed to go to a clinic in Lancaster, Pa., near their homes, and drink a rich milkshake that was made mostly of heavy cream. Over the next six hours, a group of investigators took samples of their blood, determining how much fat was churning through their bloodstreams.
Most of the study participants responded as expected — their levels of triglycerides, a common form of fat in the blood, rose steadily for three to four hours and then declined. But about 5 percent had an extraordinary reaction: their triglyceride levels started out low and hardly budged.
It turns out, the researchers report in the Friday issue of the journal Science, that those individuals who barely responded have a mutation that disables one of their two copies of a gene called apoC-III. The gene codes for a protein, APOC3, that normally slows the breakdown of triglycerides.
With the mutated gene, people break down triglycerides unusually quickly. And, the investigators find, they also have low levels of LDL cholesterol, which at high levels increases heart disease risk. They have high levels of HDL cholesterol, which is associated with a decreased risk of heart disease. And they appear to have arteries relatively clear of plaque.
To find the gene mutation, the researchers, led by Toni I. Pollin, an assistant professor of medicine at the University of Maryland School of Medicine, scanned the entire genomes of their study subjects, looking for genetic regions that were linked to levels of blood triglycerides. That led them to a region containing the apoC-III gene. When they sequenced it, they found the mutation that destroyed its function.
Dr. Alan R. Shuldiner, head of the division of endocrinology, diabetes and nutrition at the University of Maryland School of Medicine in Baltimore and the senior author of the paper, said that the Amish were ideal for the study because they were an isolated population that had been in this country for 14 generations and whose members shared many genes.
In this case, Dr. Pollin said, she and her colleagues traced the apoC-III mutation to a member of the Amish community who was born in the 18th century.
The gene is also regulated by insulin, noted Dr. Daniel J. Rader, a heart disease researcher at the University of Pennsylvania, and people with diabetes have high levels of APOC3, high levels of triglycerides and an increased risk of heart disease.
The discovery of the gene mutation, researchers say, helps bolster the case that triglycerides are related to risk of heart disease and that APOC3 is an important contributor. But clinical applications may be years away.
Dr. Ira J. Goldberg, chief of the division of preventive medicine and nutrition at Columbia, said the triglyceride case had mostly rested on studies showing an association between high triglyceride levels and an increased incidence of heart disease. But that, Dr. Goldberg added, is not cause and effect. The new study provides more direct evidence.
“Here we have a group of people with a genetic mutation that lowers triglycerides,” Dr. Goldberg said. “They seem to have less cardiovascular disease.”
As for apoC-III, the study clarifies its role, said Dr. Alan R. Tall, head of the molecular medicine division at Columbia. “It was known from animal studies that apoC-III might have a role like this,” Dr. Tall said. “But the human information is really novel. We suspected it might be the case but this nails it down.”
Dr. Rader agreed. “This is among the strongest human evidence we have that APOC3 is quote, unquote, bad,” he said. “If you had a drug to turn off the gene to prevent as much APOC3 being made, this study suggests that that would be beneficial to do.” But he added that there were no such drugs on the immediate horizon.
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