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

Author

Listed:
  • Kiran Musunuru

    (Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
    Broad Institute
    Johns Hopkins University School of Medicine)

  • 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
    University Medical Center Hamburg-Eppendorf)

  • 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
    Broad Institute)

  • 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
    Program in Cardiovascular Translational Genomics, Lillehei Heart Institute, University of Minnesota)

  • 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
    Broad Institute)

  • 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
    Broad Institute)

  • Sekar Kathiresan

    (Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
    Broad Institute)

  • Daniel J. Rader

    (Institute for Translational Medicine and Therapeutics, Institute for Diabetes, Obesity and Metabolism, and Cardiovascular Institute, University of Pennsylvania School of Medicine)

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.

Suggested Citation

  • 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 Muchm, 2010. "From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus," Nature, Nature, vol. 466(7307), pages 714-719, August.
    • Handle: RePEc:nat:nature:v:466:y:2010:i:7307:d:10.1038_nature09266
    DOI: 10.1038/nature09266
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    Cited by:

    1. Mike Thompson & Mary Grace Gordon & Andrew Lu & Anchit Tandon & Eran Halperin & Alexander Gusev & Chun Jimmie Ye & Brunilda Balliu & Noah Zaitlen, 2022. "Multi-context genetic modeling of transcriptional regulation resolves novel disease loci," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Rashid Mir & Faris J. Tayeb & Jameel Barnawi & Mohammed M. Jalal & Nizar H. Saeedi & Abdullah Hamadi & Malik A. Altayar & Sanad E. Alshammari & Nabil Mtiraoui & Mohammed Eltigani Ali & Faisel M. Abu D, 2022. "Biochemical Characterization and Molecular Determination of Estrogen Receptor-α (ESR1 PvuII-rs2234693 T>C) and MiRNA-146a (rs2910164 C>G) Polymorphic Gene Variations and Their Association with the Ris," IJERPH, MDPI, vol. 19(5), pages 1-14, March.

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