Errors in single gene may protect against heart disease

PUBLIC RELEASE DATE:

12-Nov-2014

Contact: Julia Evangelou Strait straitj@wustl.edu 314-286-0141 Washington University School of Medicine @WUSTLmed

Rare mutations that shut down a single gene are linked to lower cholesterol levels and a 50 percent reduction in the risk of heart attack, according to new research from Washington University School of Medicine in St. Louis, the Broad Institute at Massachusetts Institute of Technology and Harvard, and other institutions.

The gene, called NPC1L1, is of interest because it is the target of the drug ezetimibe, often prescribed to lower cholesterol.

The study appears Nov. 12 in The New England Journal of Medicine.

Everyone inherits two copies of most genes -- one copy from each parent. In the study, the researchers found that people with one inactive copy of NPC1L1 appeared to be protected against high LDL cholesterol --the so-called "bad" cholesterol -- and coronary heart disease, a narrowing of the heart's arteries that can lead to heart attacks.

"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, MD, PhD, 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."

The investigators mined genetic data from large clinical trials to find individuals with naturally occurring mutations in the NPC1L1 gene that completely shut it down. They analyzed multiple existing studies, pooling data from about 113,000 people. Of these trial participants, only 82 were found to have a mutation that shut off one copy of the NPC1L1 gene. No one had two inactive copies of NPC1L1. Based on a subset of data in the analysis, the researchers estimate roughly 1 in 650 people carry one inactive version of the gene.

The investigators found that people with only one working copy of the gene had LDL cholesterol levels an average of 12 milligrams per deciliter lower than the wider population of people with two working copies of the gene. This approximately 10 percent reduction in LDL cholesterol is comparable to that seen in patients taking ezetimibe. But beyond simply lowering cholesterol, the 82 people with inactive copies also had about half the risk of coronary heart disease as people with two functional copies of the gene.

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Errors in single gene may protect against heart disease