title: From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus.
abstract: 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.
authors.affiliation: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Musunuru
authors.forename: Alanna
authors.initials: A
authors.lastname: Strong
authors.forename: Maria
authors.initials: M
authors.lastname: Frank-Kamenetsky
authors.forename: Noemi E
authors.initials: NE
authors.lastname: Lee
authors.forename: Tim
authors.initials: T
authors.lastname: Ahfeldt
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Sachs
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kuperwasser
authors.forename: Vera M
authors.initials: VM
authors.lastname: Ruda
authors.forename: James P
authors.initials: JP
authors.lastname: Pirruccello
authors.forename: Brian
authors.initials: B
authors.lastname: Muchmore
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prokunina-Olsson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hall
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Morales
authors.forename: Sissel
authors.initials: S
authors.lastname: Lund-Katz
authors.forename: Michael C
authors.initials: MC
authors.lastname: Phillips
authors.forename: Jamie
authors.initials: J
authors.lastname: Wong
authors.forename: William
authors.initials: W
authors.lastname: Cantley
authors.forename: Timothy
authors.initials: T
authors.lastname: Racie
authors.forename: Kenechi G
authors.initials: KG
authors.lastname: Ejebe
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
authors.forename: Chad A
authors.initials: CA
authors.lastname: Cowan
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: 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
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D022762:CCAAT-Enhancer-Binding Proteins; D008078:Cholesterol, LDL; D008055:Lipids; D008079:Lipoproteins, VLDL; D000099183:Sortilin