UW-Milwaukee: Researcher part of team tracing genetic mutation linked to lower LDL cholesterol

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, including the University of Wisconsin-Milwaukee.

Paul Auer, assistant professor of biostatistics in the Joseph J. Zilber School of Public Health, was one of the researchers involved and a co-author of the study, which appeared Nov. 12 in the New England Journal of Medicine.

The gene, NPC1L1, is of interest because it is the target of the drug ezetimibe, often prescribed to lower cholesterol, according to a news release from Washington University School 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, according to the release.

“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 in the news release. “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.”

“There had been some confusion about whether lower LDL cholesterol will reduce the risk of heart attack,” Auer said. His research work focuses on studying genomes to help understand the genetic factors involved in chronic diseases.

The study showed that lower LDL is definitely linked to lower risk of heart disease, he added. “It’s important because we found a genetic mutation that works in a very similar way to a current medication that does reduce LDL cholesterol levels.”

Clinical trials of the drug ezetimibe are underway. However, further research will be needed to determine if the use of a medication over a limited period of time is the same as having the lifelong protection the genetic mutation provides.

“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 target NPC1L1 remains an open question.”

Auer worked with many members of the same team and much of the same data on a study published earlier this year showing that those with lower triglycerides because of another genetic mutation also had a lowered risk of heart disease.

In the LDL study published in the NEJM, according to the news release, 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 one 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.

The individuals with the rare gene mutations did not appear to differ from the larger population in any other ways, including in measures of blood pressure, body mass index and rates of diabetes.

“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, MD, 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.”

The work was supported by funding from the National Heart, Lung and Blood Institute (NHLBI) and the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) and research grants from other institutions and corporations.