Inactivating mutations in NPC1L1 and protection from coronary heart disease.
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.).
Cardiovascular Division, Department of Medicine, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
Nathan O
NO
Stitziel
Hong-Hee
HH
Won
Alanna C
AC
Morrison
Gina M
GM
Peloso
Ron
R
Do
Leslie A
LA
Lange
Pierre
P
Fontanillas
Namrata
N
Gupta
Stefano
S
Duga
Anuj
A
Goel
Martin
M
Farrall
Danish
D
Saleheen
Paola
P
Ferrario
Inke
I
König
Rosanna
R
Asselta
Piera A
PA
Merlini
Nicola
N
Marziliano
Maria Francesca
MF
Notarangelo
Ursula
U
Schick
Paul
P
Auer
Themistocles L
TL
Assimes
Muredach
M
Reilly
Robert
R
Wilensky
Daniel J
DJ
Rader
G Kees
GK
Hovingh
Thomas
T
Meitinger
Thorsten
T
Kessler
Adnan
A
Kastrati
Karl-Ludwig
KL
Laugwitz
David
D
Siscovick
Jerome I
JI
Rotter
Stanely L
SL
Hazen
Russell
R
Tracy
Sharon
S
Cresci
John
J
Spertus
Rebecca
R
Jackson
Stephen M
SM
Schwartz
Pradeep
P
Natarajan
Jacy
J
Crosby
Donna
D
Muzny
Christie
C
Ballantyne
Stephen S
SS
Rich
Christopher J
CJ
O'Donnell
Goncalo
G
Abecasis
Shamil
S
Sunaev
Deborah A
DA
Nickerson
Julie E
JE
Buring
Paul M
PM
Ridker
Daniel I
DI
Chasman
Erin
E
Austin
Iftikhar J
IJ
Kullo
Peter E
PE
Weeke
Christian M
CM
Shaffer
Lisa A
LA
Bastarache
Joshua C
JC
Denny
Dan M
DM
Roden
Colin
C
Palmer
Panos
P
Deloukas
Dan-Yu
DY
Lin
Zheng-zheng
ZZ
Tang
Jeanette
J
Erdmann
Heribert
H
Schunkert
John
J
Danesh
Jaume
J
Marrugat
Roberto
R
Elosua
Diego
D
Ardissino
Ruth
R
McPherson
Hugh
H
Watkins
Alex P
AP
Reiner
James G
JG
Wilson
David
D
Altshuler
Richard A
RA
Gibbs
Eric S
ES
Lander
Eric
E
Boerwinkle
Stacey
S
Gabriel
Sekar
S
Kathiresan
D000328:Adult; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000097:blood*; D003327:Coronary Disease / Q000235:genetics*; D005091:Exons; D005260:Female; D020868:Gene Silencing; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009154:Mutation; D011487:Protein Conformation; D012306:Risk; D017422:Sequence Analysis, DNA; D014280:Triglycerides / Q000097:blood; D044465:White People / Q000235:genetics
D008078:Cholesterol, LDL; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; D014280:Triglycerides