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 CantleyTimothy Racie, Kenechi G. Ejebe, Marju Orho-Melander, Olle Melander, Victor Koteliansky, Kevin Fitzgerald, Ronald M. Krauss, Chad A. Cowan, Sekar Kathiresan, Daniel J. Rader

Research output: Contribution to journalArticlepeer-review

709 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)714-719
Number of pages6
JournalNature
Volume466
Issue number7307
DOIs
StatePublished - Aug 5 2010

Bibliographical note

Funding Information:
Acknowledgements We thank D. Altshuler, E. Fisher and J. Maraganore for advice and guidance, and A. Akinc, J. Billheimer, R. Brown, R. Camahort, D. Cromley, E. Eduoard, I. Fuki, C. Geaney, G. Hinkle, I. Kohaar, S. Kuchimanchi, W. Lagor, F. Lau, D. Lum, M. Maier, D. Marchadier, R. Meyers, J. Millar, S. Milstein, D. Nguyen, D. Perez, D. Peters, V. Redon, A. Rigamonti, R. Schinzel, M.-S. Sun, S.-A. Toh, A. Wilson and K. Wojnoonski for assistance and suggestions. We acknowledge the National Heart, Lung, and Blood Institute (NHLBI) Gene Therapy Resource Program for providing support for viral vector production as well as the Vector Core laboratory of the University of Pennsylvania for producing the vectors. We acknowledge the members of the NHLBI Candidate Gene Association Resource (CARe) lipids working group for the contribution of association data in African Americans. This work was supported in part by a T32 grant in Cell and Molecular Training for Cardiovascular Biology from the United States National Institutes of Health (NIH), K99-HL098364 from the NIH, and the Clinician Scientist Program of the Harvard Stem Cell Institute (K.M.); a Medical Scientist Training Program grant from the NIH (A.S.); the intramural research program of the Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH (L.P.-O.); the Swedish Medical Research Council, Heart-Lung Foundation, and Påhlsson Foundation (M.O.-M., O.M.); U01-HL069757 from the NIH and research support from Quest Diagnostics, Inc. (R.M.K.); RC2-HL101864 from the NIH (S.K.); and P01-HL059407 and RC2-HL101864 from the NIH and a ‘‘Freedom to Discover’’ Unrestricted Cardiovascular Research Grant from Bristol-Myers Squibb (D.J.R.).

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

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