Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease

被引：318

作者：

Stitziel, Nathan O. ^{[1
,2
]}

Won, Hong-Hee ^{[4
,5
,7
,11
]}

Morrison, Alanna C. ^{[13
]}

Peloso, Gina M. ^{[4
,5
,7
,11
]}

Do, Ron ^{[4
,5
,7
,11
]}

Lange, Leslie A. ^{[16
]}

Fontanillas, Pierre ^{[11
]}

Gupta, Namrata ^{[11
]}

Duga, Stefano ^{[18
]}

Goel, Anuj ^{[21
,22
]}

Farrall, Martin ^{[21
,22
]}

Saleheen, Danish ^{[28
,30
]}

Ferrario, Paola ^{[31
]}

Koenig, Inke ^{[31
]}

Asselta, Rosanna ^{[18
]}

Merlini, Piera A. ^{[19
,20
]}

Marziliano, Nicola ^{[19
]}

Notarangelo, Maria Francesca ^{[19
]}

Schick, Ursula ^{[39
]}

Auer, Paul ^{[44
]}

Assimes, Themistocles L. ^{[45
,46
]}

Reilly, Muredach ^{[29
]}

Wilensky, Robert ^{[29
]}

Rader, Daniel J. ^{[27
]}

Hovingh, G. Kees ^{[48
]}

Meitinger, Thomas ^{[34
,35
,38
]}

Kessler, Thorsten ^{[37
]}

Kastrati, Adnan ^{[37
,38
]}

Laugwitz, Karl-Ludwig ^{[36
,38
]}

Siscovick, David ^{[40
,41
]}

Rotter, Jerome I. ^{[47
]}

Hazen, Stanley L. ^{[49
]}

Tracy, Russell ^{[51
,52
]}

Cresci, Sharon ^{[1
,3
]}

Spertus, John ^{[53
]}

Jackson, Rebecca ^{[50
]}

Schwartz, Stephen M. ^{[39
,42
]}

Natarajan, Pradeep ^{[4
,5
,7
,11
]}

Crosby, Jacy ^{[13
]}

Muzny, Donna ^{[14
]}

Ballantyne, Christie ^{[15
]}

Rich, Stephen S. ^{[54
]}

O'Donnell, Christopher J. ^{[6
,7
,12
]}

Abecasis, Goncalo ^{[55
]}

Sunyaev, Shamil ^{[8
,11
]}

Nickerson, Deborah A. ^{[43
]}

Buring, Julie E. ^{[9
,10
,32
,33
]}

Ridker, Paul M. ^{[9
,10
]}

Chasman, Daniel I. ^{[9
,10
]}

Austin, Erin ^{[56
]}

机构：

[1] Washington Univ, Sch Med, Dept Med, Div Cardiovasc, St Louis, MO 63130 USA

[2] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63130 USA

[3] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[4] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA

[5] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA

[6] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA

[7] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA

[8] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[9] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Boston, MA USA

[11] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[12] NHLBI, Framingham Heart Study, Framingham, MA USA

[13] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA

[14] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[15] Baylor Coll Med, Sect Atherosclerosis & Vasc Med, Houston, TX 77030 USA

[16] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

[17] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA

[18] Univ Milan, Dipartimento Biotecnol Med & Med Traslaz, Milan, Italy

[19] Azienda Osped Univ Parma, Parma, Italy

[20] Assoc Studio Trombosi Cardiol, Pavia, Italy

[21] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England

[22] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[23] Univ Cambridge, Cambridge, England

[24] Wellcome Trust Sanger Inst, Cambridge, England

[25] Univ Dundee, Med Res Inst, Dundee, Scotland

[26] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England

[27] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[28] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA

[29] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA

[30] Ctr Noncommunicable Dis, Karachi, Pakistan

[31] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany

[32] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23538 Lubeck, Germany

[33] DZHK German Res Ctr Cardiovasc Res Partner Site H, Lubeck, Germany

[34] Helmholtz Zentrum, Inst Humangenet, Neuherberg, Germany

[35] Tech Univ Munich, Klinikum Rechts Isar, Inst Humangenet, D-80290 Munich, Germany

[36] Tech Univ Munich, Klinikum Rechts Isar, Med Klin, D-80290 Munich, Germany

[37] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany

[38] Partner Site Munich Heart Alliance, German Ctr Cardiovasc Res DZHK, Munich, Germany

[39] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA

[40] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA

[41] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA

[42] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[43] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[44] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA

[45] Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA

[46] Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA

[47] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA

[48] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands

[49] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA

[50] Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2014年 / 371卷 / 22期

基金：

美国国家卫生研究院;

关键词：

GENETIC-VARIANTS; CHOLESTEROL; EZETIMIBE; RISK; LDL; SIMVASTATIN; ABSORPTION; RATIONALE; EFFICACY; DESIGN;

D O I：

10.1056/NEJMoa1405386

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：2072 / 2082

页数：11