Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease
Open accessAbstract
BACKGROUND: Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann-Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. METHODS: We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. RESULTS: With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P=0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P=0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). CONCLUSIONS: Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.).
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A genetic sequencing study involving more than 90,000 patients found significantly lower LDL-C levels and a lower risk of coronary heart diseases among patients with NPC1L1 mutations.
“A genetic sequencing study involving more than 90,000 patients found significantly lower LDL-C levels and a lower risk of coronary heart diseases among patients with NPC1L1 mutations [58]”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [58]
The Abstract Results report significantly lower LDL cholesterol and lower coronary heart disease risk among carriers of inactivating NPC1L1 mutations. The Abstract Methods and Results specify that 22,092 people were sequenced and another 91,002 were genotyped; the full study included 113,094 participants, but only 29,954 had coronary heart disease. Thus, the finding is supported, but the description of more than 90,000 patients in a sequencing study is imprecise. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPolymorphisms affecting NPC1L1 are associated with both lower levels of LDL cholesterol and a lower risk of cardiovascular events.
“Polymorphisms affecting NPC1L1 are associated with both lower levels of LDL cholesterol and a lower risk of cardiovascular events.19”
From Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes (2015) · cites this paper as [19]
The Abstract Results and Discussion report that carriers of rare, inactivating NPC1L1 mutations had lower LDL cholesterol and a lower risk of coronary heart disease. The claim is broader: the paper does not establish these associations for NPC1L1 polymorphisms generally or for cardiovascular events beyond coronary heart disease. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThere is no clear evidence that statins have a clinically significant beneficial or adverse effect on renal function.
“There is no clear evidence that statins have a clinically significant beneficial or adverse effect on renal function [253].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [253]
A systematic review of 22 studies including 3465 patients with functioning kidney transplants and no CHD concluded that statins may reduce cardiovascular events.
“A systematic review of the benefits and harms of statins in patients with a functioning kidney transplant included 3465 patients, free of CHD, from 22 studies. Although the authors concluded that statins may reduce CV events, they also suggested a need for additional studies [253].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [253]
That systematic review also suggested that additional studies are needed.
“A systematic review of the benefits and harms of statins in patients with a functioning kidney transplant included 3465 patients, free of CHD, from 22 studies. Although the authors concluded that statins may reduce CV events, they also suggested a need for additional studies [253].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [253]
Naturally occurring mutations that inactivate NPC1L1 are associated with reduced plasma LDL-C and reduced risk of CAD.
“Naturally occurring mutations that inactivate the protein were found to be associated with reduced plasma LDL-C and reduced risk for CAD.”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [245]
A lifelong reduction of only 11% in plasma LDL-cholesterol levels due to loss-of-function mutations in NPC1L1 causes a striking 53% reduction in myocardial infarction.
“Similarly, a lifelong reduction of only 11% in plasma LDL-cholesterol levels due to loss-of-function mutations in NPC1L1, an intestinal cholesterol transporter, causes a striking 53% reduction in myocardial infarction (37).”
From Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms (2018) · cites this paper as [37]
Naturally occurring mutations that inactivate NPC1L1 are associated with reduced plasma LDL cholesterol and reduced risk for coronary artery disease.
“Naturally occurring mutations that inactivate the protein were found to be associated with reduced plasma LDL-C and reduced risk for CAD.245”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [245]
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- Authors
- The Myocardial Infarction Genetics Consortium Investigators
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- The Myocardial Infarction Genetics Consortium Investigators
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-11-27
- Volume
- 371
- Issue
- 22
- Pages
- 2072-2082
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4335708
- OpenAlex
- W2478496979
- Cited by
- 419
- References
- 41
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 13 · 2023: 21 · 2022: 19 · 2021: 26 · 2020: 36 · 2019: 44 · 2018: 31 · 2017: 47 · 2016: 84 · 2015: 73 · 2014: 5
- FWCI
- 69.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0512-10165)
- British Heart Foundation (RG/08/014/24067)
- National Institutes of Health (UL1TR000124)
- Canadian Institutes of Health Research
- Medical Research Council (MR/L003120/1)
- National Institute on Aging (U01AG049505)
- National Heart, Lung, and Blood Institute (RC2HL102925, K08HL114642, RC2HL102926, R01HL107816, T32HL007208)
- National Human Genome Research Institute (U54HG003067, U01HG006378)
- National Cancer Institute (R01CA082659)
- National Institute of Nursing Research (R01NR013396)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063491)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- NPC1L1, loss-of-function mutations, coronary artery disease, ezetimibe, LDL cholesterol, plasma lipids, genetic variants, therapeutic target, LDL cholesterol lowering
- MeSH terms
- Adult, Coronary Disease, Exons, Female, Genotype, Humans, Cholesterol, LDL, Male, Membrane Proteins, Middle Aged, Mutation, Protein Conformation, Risk, Triglycerides, Case-Control Studies, Sequence Analysis, DNA, Gene Silencing, Membrane Transport Proteins, Black People, White People, Asian People
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