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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / biosynthesis
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Adaptor Proteins, Vesicular Transport / deficiency
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / metabolism*
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Animals
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Base Sequence
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Binding Sites
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CCAAT-Enhancer-Binding Proteins / metabolism
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Cells, Cultured
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Cholesterol, LDL / blood
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Cholesterol, LDL / metabolism*
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Chromosomes, Human, Pair 1 / genetics*
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Cohort Studies
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Coronary Artery Disease / blood
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Coronary Artery Disease / genetics
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Europe / ethnology
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Gene Expression Regulation
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Gene Knockdown Techniques
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Genetic Predisposition to Disease / genetics*
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Genome-Wide Association Study
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Haplotypes / genetics
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Hepatocytes / metabolism
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Humans
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Lipids / blood
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Lipoproteins, VLDL / blood
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Lipoproteins, VLDL / metabolism
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Liver / cytology
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Liver / metabolism
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Mice
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Myocardial Infarction / blood
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Myocardial Infarction / genetics
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Phenotype
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Polymorphism, Single Nucleotide / genetics*
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Transcription, Genetic
Substances
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Adaptor Proteins, Vesicular Transport
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CCAAT-Enhancer-Binding Proteins
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Cholesterol, LDL
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Lipids
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Lipoproteins, VLDL
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sortilin