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

Kiran Musunuru, Alanna Strong, Maria Frank-Kamenetsky, Noemi E. Lee, Tim Ahfeldt, Katherine V. Sachs, Xiaoyu Li, Hui Li, Nicolas Kuperwasser, Vera M. Ruda, James P. Pirruccello, Brian Muchmore, Ludmila Prokunina-Olsson, Jennifer L. Hall, Eric E. Schadt, Carlos R. Morales, Sissel Lund-Katz, Michael C. Phillips, Jamie Wong, William Cantley, Timothy Racie, Kenechi G. Ejebe, Marju Orho-Melander, Olle Melander, Victor Koteliansky, Kevin Fitzgerald, Ronald M. Krauss, Chad A. Cowan, Sekar Kathiresan () and Daniel J. Rader ()
Additional contact information
Kiran Musunuru: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
Alanna Strong: Institute for Translational Medicine and Therapeutics, Institute for Diabetes, Obesity and Metabolism, and Cardiovascular Institute, University of Pennsylvania School of Medicine
Maria Frank-Kamenetsky: Alnylam Pharmaceuticals, Inc.
Noemi E. Lee: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
Tim Ahfeldt: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
Katherine V. Sachs: Institute for Translational Medicine and Therapeutics, Institute for Diabetes, Obesity and Metabolism, and Cardiovascular Institute, University of Pennsylvania School of Medicine
Xiaoyu Li: Institute for Translational Medicine and Therapeutics, Institute for Diabetes, Obesity and Metabolism, and Cardiovascular Institute, University of Pennsylvania School of Medicine
Hui Li: Institute for Translational Medicine and Therapeutics, Institute for Diabetes, Obesity and Metabolism, and Cardiovascular Institute, University of Pennsylvania School of Medicine
Nicolas Kuperwasser: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
Vera M. Ruda: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
James P. Pirruccello: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
Brian Muchmore: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Ludmila Prokunina-Olsson: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health
Jennifer L. Hall: Broad Institute
Eric E. Schadt: Sage Bionetworks
Carlos R. Morales: McGill University
Sissel Lund-Katz: The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine
Michael C. Phillips: The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine
Jamie Wong: Alnylam Pharmaceuticals, Inc.
William Cantley: Alnylam Pharmaceuticals, Inc.
Timothy Racie: Alnylam Pharmaceuticals, Inc.
Kenechi G. Ejebe: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
Marju Orho-Melander: Skania University Hospital, Lund University
Olle Melander: Skania University Hospital, Lund University
Victor Koteliansky: Alnylam Pharmaceuticals, Inc.
Kevin Fitzgerald: Alnylam Pharmaceuticals, Inc.
Ronald M. Krauss: Children’s Hospital Oakland Research Institute
Chad A. Cowan: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
Sekar Kathiresan: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
Daniel J. Rader: Institute for Translational Medicine and Therapeutics, Institute for Diabetes, Obesity and Metabolism, and Cardiovascular Institute, University of Pennsylvania School of Medicine

Nature, 2010, vol. 466, issue 7307, 714-719

Abstract: 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.

Date: 2010
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/nature09266 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:466:y:2010:i:7307:d:10.1038_nature09266

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature09266

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().