Inactivating mutations in NPC1L1 and protection from coronary heart disease

Stitziel NO, Won HH, Morrison AC, Peloso GM, Do R, Lange LA, Fontanillas P, Gupta N, Duga S, Goel A, Farrall M, Saleheen D, Ferrario P, Koenig I, Asselta R, Merlini PA, Marziliano N, Notarangelo MF, Schick U, Auer P, Assimes TL, Reilly M, Wilensky R, Rader DJ, Hovingh GK, Meitinger T, Kessler T, Kastrati A, Laugwitz KL, Siscovick D, Rotter JI, Hazen SL, Tracy R, Cresci S, Spertus J, Jackson R, Schwartz SM, Natarajan P, Crosby J, Muzny D, Ballantyne C, Rich SS, O'Donnell CJ, Abecasis G, Sunyaev S, Nickerson DA, Buring JE, Ridker PM, Chasman DI, Austin E, Ye Z, Kullo IJ, Weeke PE, Shaffer CM, Bastarache LA, Denny JC, Roden DM, Palmer C, Deloukas P, Lin DY, Tang ZZ, Erdmann J, Schunkert H, Danesh J, Marrugat J, Elosua R, Ardissino D, Mcpherson R, Watkins H, Reiner AP, Wilson JG, Altshuler D, Gibbs RA, Lander ES, Boerwinkle E, Gabriel S, Kathiresan S (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Book Volume: 371

Pages Range: 2072-2082

Journal Issue: 22

DOI: 10.1056/NEJMoa1405386

Abstract

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.)

Involved external institutions

Washington University in St. Louis United States (USA) (US) Harvard University United States (USA) (US) University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US) University of North Carolina at Chapel Hill United States (USA) (US) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) Università degli studi di Milano Italy (IT) University of Oxford United Kingdom (GB) University of Pennsylvania United States (USA) (US) Universität zu Lübeck Germany (DE) Azienda Ospedaliero-Universitaria di Parma / Parma University Hospital Italy (IT) Stanford University United States (USA) (US) University of Amsterdam Netherlands (NL) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) Technische Universität München (TUM) Germany (DE) University of Washington United States (USA) (US) Harbor–UCLA Medical Center United States (USA) (US) Cleveland Clinic United States (USA) (US) University of Vermont United States (USA) (US) University of Missouri–Kansas City (UMKC) United States (USA) (US) Ohio State University United States (USA) (US) Houston Texas Medical Center United States (USA) (US) University of Virginia (UVA) United States (USA) (US) University of Michigan United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) Mayo Clinic United States (USA) (US) Vanderbilt University United States (USA) (US) University of Dundee United Kingdom (GB) Wellcome Trust Sanger Institute - Genome Research Limited United Kingdom (GB) University of Cambridge United Kingdom (GB) IMIM: Institut Hospital del Mar d'Investigacions Mèdiques Spain (ES) Fred Hutchinson Cancer Research Center United States (USA) (US) University of Wisconsin - Madison United States (USA) (US) University of Mississippi (Ole Miss) United States (USA) (US) University of Ottawa Canada (CA)

How to cite

APA:

Stitziel, N.O., Won, H.-H., Morrison, A.C., Peloso, G.M., Do, R., Lange, L.A.,... Kathiresan, S. (2014). Inactivating mutations in NPC1L1 and protection from coronary heart disease. New England Journal of Medicine, 371(22), 2072-2082. https://doi.org/10.1056/NEJMoa1405386

MLA:

Stitziel, Nathan O., et al. "Inactivating mutations in NPC1L1 and protection from coronary heart disease." New England Journal of Medicine 371.22 (2014): 2072-2082.

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