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

849 Scopus citations


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
Pages (from-to)714-719
Number of pages6
Issue number7307
StatePublished - 5 Aug 2010
Externally publishedYes


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