From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus.
Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP (CCAAT/enhancer binding protein) transcription factor binding site and alters the hepatic expression of the SORT1 gene. With small interfering RNA (siRNA) knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes.
Musunuru
Kiran
K
Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Strong
Alanna
A
Frank-Kamenetsky
Maria
M
Lee
Noemi E
NE
Ahfeldt
Tim
T
Sachs
Katherine V
KV
Li
Xiaoyu
X
Li
Hui
H
Kuperwasser
Nicolas
N
Ruda
Vera M
VM
Pirruccello
James P
JP
Muchmore
Brian
B
Prokunina-Olsson
Ludmila
L
Hall
Jennifer L
JL
Schadt
Eric E
EE
Morales
Carlos R
CR
Lund-Katz
Sissel
S
Phillips
Michael C
MC
Wong
Jamie
J
Cantley
William
W
Racie
Timothy
T
Ejebe
Kenechi G
KG
Orho-Melander
Marju
M
Melander
Olle
O
Koteliansky
Victor
V
Fitzgerald
Kevin
K
Krauss
Ronald M
RM
Cowan
Chad A
CA
Kathiresan
Sekar
S
Rader
Daniel J
DJ
D033942:Adaptor Proteins, Vesicular Transport / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000097:blood / Q000378:metabolism*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics; D005060:Europe / Q000208:ethnology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014158:Transcription, Genetic; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D022762:CCAAT-Enhancer-Binding Proteins; D008078:Cholesterol, LDL; D008055:Lipids; D008079:Lipoproteins, VLDL; D000099183:Sortilin