Physicians' Academy for Cardiovascular Education

Inactivating mutations in gut cholesterol transporter lower LDL-c levels and CHD risk

Literature - The Myocardial Infarction Genetics Consortium Investigators, NEJM 2014


Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease

The Myocardial Infarction Genetics Consortium Investigators.
N Engl J Med. 2014 Nov 12. [Epub ahead of print]


Ezetimibe inhibits the function of the Niemann-Pick C1-like (NPC1L1) protein, coded for by the NPC1L1-gene [1]. NPC1L1 functions as a transporter of dietary cholesterol from the gut lumen into intestinal enterocytes [2,3]. Ezetimibe inhibits cholesterol absorption by about 50% [4], resulting in 15 to 20% lower plasma LDL cholesterol levels [5].
Genomewide association studies have identified polymorphisms in NPC1L1 that were associated with modest alterations in LDL-c levels [6]. Of these type of DNA variants, it is difficult to determine how they affect gene activity. On the other hand, the effect of some DNA mutations in the protein-coding sequence may be easier to predict, for instance when it concerns an inactivating mutation. These type of mutations, are generally rare as a consequence of natural selection.
This study tested the hypothesis that protein-inactivating mutations in NPC1L1 reduce both the LDL-c level and the risk of coronary heart disease (CHD). To this extent, the coding region of NPC1L1 was sequenced in many individuals with or without known CHD. LDL-c levels and risk of CHD was compared between heterozygous NPC1L1-mutation carriers and noncarriers.

Main results

  • 15 mutations expected to inactivate NPC1L1 were identified during sequencing NPC1L1 in 7364 patients with CHD and in 14728 controls. These 15 mutations were seen in 34 individuals, all heterozygotes (~1 in 650).
  • The most frequently detected mutation was p.Arg406X (allele frequency: 0.02% in Europan participants) was genotyped in 22.590 additional participants with CHD and in 68.412 controls, yielding 48 heterozygous carriers.
  • Carriers of NPC1L1-inactivating mutations had significantly lower levels of total cholesterol (mean adjusted difference: -13 mg/dL (0.34 mmol/L), P=0.03) than noncarriers.
    LDL-c levels were also lower in carriers (mean adj. difference: -12 mg/dL (0.31 mmol/L), P=0.04) than in noncarriers.
    Triglyceride levels were no significantly reduced in carriers (-12%, P=0.11).
  • HDL cholesterol levels were not significantly different between carriers and noncarriers of NPC1L1-inactivating mutations (carriers: +2 mg/dL (0.05 mmol/L), P=0.29).
  • The magnitude of LDL reduction was similar for participants of European and African ancestry (-13 mg/dL and -10 mg/dL, respectively).
  • Carriers of the 15 NPC1L1-inactivating mutations were underrepresented among patients with coronary heart disease (11/29.954, 0.04%), as compared with controls (71/83.140, 0.09%). Thus, carriers of NPC1L1-inactivating mutations show a 53% reduction in the risk of CHD (OR: 0.47, 95%CI: 0.25-0.87, P=0.008). A reduced risk of CHD was see both for participants of European (57% risk reduction) and African (17% risk reduction) descent.


This study identified fifteen rare NPC1L1 mutations that were expected to disrupt protein function. Carriers of these NPC1L1-inactivating mutations indeed had a lower mean LDL-c level, and a 53% lower risk of coronary heart disease. These findings imply that lifelong inactivation of one copy of NPC1L1 is protective against CHD.
The observed risk reduction among carriers exceeds the reduction that would have been expected for a decrease of 12 mg/dL based on statin trials. This could be because modestly reduced lipid levels over a lifetime may result in a larger risk reduction than pharmacological treatment later in life.
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1. Garcia-Calvo M, Lisnock J, Bull HG, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci U S A 2005;102:8132-7.
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3. Altmann SW, Davis HR Jr, Zhu LJ, et al. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science 2004;303:1201-4.
4. Sudhop T, Lütjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 2002;106:1943-8.
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6. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707-13.

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