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Lucky few. Some Amish harbor a mutation that appears to protect them from high-fat foods..

Richard T. Nowitz/Corbis

A Horse, a Buggy, and a Very Decadent Milkshake

Downing 800-calorie milkshakes is a great way to make the fat levels in your blood skyrocket. But a small proportion of Amish in Lancaster County, Pennsylvania, are not so easily affected, researchers have found. These lucky few harbor a genetic mutation that keeps their levels of fat particles called triglycerides in check and possibly protects them from heart disease. Although their particular mutation doesn't show up very often in the general population, the gene itself could play an important role in heart disease.

Researchers already know that people differ in their responses to fatty foods. The body converts unused calories from meals into triglycerides, which can cause heart disease and stroke, and some people amass far more triglycerides than other people do. Scientists have found that genetics plays a role, but not all of the players have been identified.

University of Maryland School of Medicine geneticist Toni Pollin, endocrinologist Alan Shuldiner, and their colleagues turned to the Old Order Amish in Lancaster County, Pennsylvania--a group whose members marry each other and have little contact with the outside world. The genetic similarity among this group makes it easier to search for disease genes. The researchers were interested in how 800 of these Amish would respond to short exposures to environmental factors, such as a high-salt diet, linked to heart disease. The subjects were healthy adults, divided almost equally between men and women.

One test involved drinking a high-fat milkshake that packed a whopping 782 calories, "primarily heavy whipping cream," says Pollin. Drinking just one of these won't trigger a heart attack in the long run, but in the short term, it causes changes in triglyceride levels, much like eating a candy bar can cause a spike in blood sugar. Researchers measured the Amish subjects' triglyceride levels just before the subjects drank the shake and every hour for 6 hours afterward. As expected, some participants saw their triglycerides soar, but for others, the increase was more modest.

Then, the researchers performed a so-called genome-wide association study on the participants, searching for variations in a single DNA base correlated with these differences. That led them to a gene called APOC3; mice without this gene have low triglyceride levels. When Pollin and her colleagues sequenced the gene in their Amish volunteers, they found a mutation that matched with those who had lower triglycerides to start with and whose blood levels changed relatively little after drinking the milkshake. Five percent of the cohort had this mutation, and further study found that they had in their blood about half the amount of apoC-III, the protein produced by the gene APOC3. Having less of this protein means triglycerides get cleared from the blood more quickly (the protein decreases the liver's uptake of fatty particles), explaining the lower blood fat levels in the Amish subgroup. The APOC3 mutation carriers also had little calcification of their coronary arteries, a measure of early atherosclerosis, as compared with those who didn't carry the mutation, the researchers report in tomorrow's issue of Science.

Anne Tybjærg-Hansen, who studies genetics and heart disease at Copenhagen University Hospital in Denmark, says the study convincingly demonstrates a link between this particular APOC3 mutation and how the body handles triglycerides. Because the Amish are so unique, however, "the mutation they found is probably not a mutation that you're going to find in other populations." Indeed, Pollin notes that her group has failed to find it in a small sample of 200 healthy Caucasians. This is also not the first gene associated with triglyceride levels, Tybjærg-Hansen says. But the work provides clear proof that APOC3 is important for triglycerides and disease risk in some people, and there may well be other mutations in the gene out there, she says.