Rare mutations that shut off a single gene were linked to reduced cholesterol and a 50 percent reduced risk of heart attack.
The gene, dubbed NPC1L1, is the target of the cholesterol drug ezetimibe, Washington University in St. Louis reported. The researchers found people with one inactive copy (everyone inherits two genes) of NPC1L1 had a stronger protection against LDL "bad" cholesterol and coronary heart disease.
"This analysis demonstrates that human genetics can guide us in terms of thinking about appropriate genes to target for clinical therapy," said first author Nathan O. Stitziel, a cardiologist at Washington University School of Medicine. "When people have one copy of a gene not working, it's a little like taking a drug their entire lives that is inhibiting this gene."
To make their findings the researchers looked at genetic information from multiple existing studies encompassing 113,000 people. Out of this sample only 82 people were found to have a mutation that shut off the copy of the NPC1L1 gene, suggesting only one in every 650 people carry one of the inactive genes.
The researchers observed people with only one working copy of the gene had LDL cholesterol levels an average of 12 milligrams per deciliter lower than those without it. The about 10 percent reduction in LDL cholesterol is comparable to patients who take ezetimibe.
"Protective mutations like the one we've just identified for heart disease are a treasure trove for understanding human biology," said senior author Sekar Kathiresan, of the Broad Institute, and director of preventive cardiology at Massachusetts General Hospital. "They can teach us about the underlying causes of disease and point to important drug targets."
Ezetimibe is known to have a cholesterol-lowering effect, but there has been debate as to whether or not it lowers the risk of heart disease.
"It's not possible to draw a direct conclusion about ezetimibe from this study," Stitziel said. "But we can say this genetic analysis gives us some confidence that targeting this gene should reduce the risk of heart attack. Whether ezetimibe specifically is the best way to targetNPC1L1 remains an open question."
The findings were published Nov. 12 in the New England Journal of Medicine.
