How a rare genetic quirk may protect against heart disease

In Lancaster County, a small percentage of the Amish have a rare genetic mutation that allows them to clear fats from the bloodstream unusually quickly.

When we eat a fatty meal, the fats are packaged into triglycerides by the intestine and put into the blood.

An enzyme on blood vessels then cleaves the triglycerides so the fats can be used for energy in the heart and skeletal muscles. Fats not used as energy are deposited in adipose tissue.

Excess blood triglycerides can be deposited in artery walls, raising the risk of heart disease, said Dan Rader, chairman of the department of genetics at the University of Pennsylvania's Perelman School of Medicine.

A gene called APOC3 contains the recipe for a protein that inhibits, or slows down, the activity of this fat-cleaving enzyme and raises the level of blood triglycerides and risk of heart disease.

But in Lancaster County, a small a small percentage of Amish people have one copy of an unusual APOC3 mutation, meaning they are unable to make the normal version of protein that inhibits the fat-cleaving enzyme. As a result, they are very efficient at clearing triglycerides from the blood.

Scientists have previously shown that people who carry one copy of this mutation are at lower risk of getting heart disease. 

Recently, researchers have identified human APOC3 "knockouts" — people in Pakistan who inherited two defective copies of this gene, one from each parent. On average, they have even lower levels of triglycerides than the Amish people with one copy.

The researchers hail from Penn, Massachusetts General Hospital, the University of Cambridge, and the Center for Non-Communicable Diseases in Karachi, Pakistan, among other institutions.

"What happens is they probably clear their triglycerides from the blood exceptionally fast," Penn's Rader said. "You take your foot off the brake, and the enzyme can act much faster to break down and clear the triglycerides."