From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus

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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.",
author = "Kiran Musunuru and Alanna Strong and Maria Frank-Kamenetsky and Lee, {Noemi E.} and Tim Ahfeldt and Sachs, {Katherine V.} and Xiaoyu Li and Hui Li and Nicolas Kuperwasser and Ruda, {Vera M.} and Pirruccello, {James P.} and Brian Muchmore and Ludmila Prokunina-Olsson and Hall, {Jennifer L.} and Schadt, {Eric E.} and Morales, {Carlos R.} and Sissel Lund-Katz and Phillips, {Michael C.} and Jamie Wong and William Cantley and Timothy Racie and Ejebe, {Kenechi G.} and Marju Orho-Melander and Olle Melander and Victor Koteliansky and Kevin Fitzgerald and Krauss, {Ronald M.} and Cowan, {Chad A.} and Sekar Kathiresan and Rader, {Daniel J.}",
year = "2010",
doi = "10.1038/nature09266",
language = "English",
volume = "466",
pages = "714--U2",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7307",