Gene Mutations in NPC1L1, the Target of the Drug Ezetimibe, Found to Reduce Cholesterol and Protect Against Heart Attack

Researchers at Washington University have shown that mutations in the gene NPC1L1 are associated with lower cholesterol and about 50% reduction in risk of heart attack. The research was led by Washington University Cardiologist Dr. Nathan Stitziel and appears online November 12th in the New England Journal of Medicine.

Ezetimibe, a drug commonly prescribed to lower LDL cholesterol, functions by inhibiting the protein product of the NPC1L1 gene. It is unknown if treatment with ezetimibe also lowers risk of heart attack. The research team performed a genetic analysis on more than 113,000 individuals to identify people who carried mutations that inactivated one copy of NPC1L1. “Inactivating mutations in gene encoding a drug target can mimic the action of an inhibitory drug can provide insight into the potential efficacy of that drug,” said the study’s lead author Nathan Stitziel, MD, PhD, Instructor in Medicine at Washington University School of Medicine. These individuals who carried inactivating mutations in NPC1L1 had 12 mg/dL lower LDL cholesterol and 53% reduced risk of heart attack compared with non-carriers. “These data suggest that pharmacologic therapies targeting NPC1L1, such as ezetimibe, should reduce the risk of heart attack,” Stitziel said. “More generally, this work demonstrates the potential of protective mutations in revealing insights into human disease and the ability to point toward important drug targets.” The research is published in the New England Journal of Medicine.