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Mutations disrupting NPC1L1 linked to lower LDL, reduced CHD risk
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Mutations that disrupt the function of the protein encoded by the NPC1L1 gene are associated with reduced plasma LDL levels and a lower risk for CHD, according to data published in The New England Journal of Medicine.
The Myocardial Infarction Genetics Consortium investigators sequenced the exons of NPC1L1 in 7,364 patients with CHD and in 14,728 controls without CHD. They also genotyped the most frequently observed inactivating mutation (p.Arg406X) in 22,590 patients with CHD and in 68,412 controls. They then tested the association between the inactivating mutations, plasma lipid levels and risk for CHD.
During sequencing, the investigators identified 15 distinct NPC1L1 inactivating mutations. Approximately one in 650 people were a heterozygous carrier for one of the mutations.
Compared with noncarriers, heterozygous carriers of NPC1L1 inactivating mutations had lower LDL levels by a mean of 12 mg/dL (P=.04).
Those who were carriers had a relative reduction of 53% in the risk for CHD (OR=0.47; 95% CI, 0.25-0.87).
Of the 29,954 patients with CHD, only 11 had an inactivating mutation (carrier frequency, 0.04%), whereas of the 83,140 controls, 71 had an inactivating mutation (carrier frequency, 0.09%).
“The observation that genetic inhibition of NPC1L1 reduces the risk [for CHD] increases the prior probability that pharmacologic inhibition of NPC1L1 will also reduce risk of disease,” the investigators wrote.
Anticipated results of IMPROVE-IT, a trial to determine whether the addition of ezetimibe (Zetia, Merck) to background simvastatin therapy reduces risk for recurrent CV events in patients with a recent ACS, will be presented at the American Heart Association Scientific Sessions.
According to the study background, ezetimibe lowers plasma levels of LDL by inhibiting activity of the NPC1L1 protein; however, it was unknown whether inhibition reduces the risk for CHD.
“Our findings do not predict with certainty that ezetimibe will be found to reduce [CV risk] in the IMPROVE-IT trial or other clinical studies,” the investigators wrote. They noted that lifelong genetic inhibition is not the same as pharmacologic inhibition initiated in adulthood and lasting for several years, that the present study focused on a first CV event and IMPROVE-IT is evaluating recurrent events, and that potential toxic effects of pharmacologic therapies are not tested in genetic studies.
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Disclosure: See the full study for a list of the funding sources and the researchers’ relevant financial disclosures.