From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus by Musunuru Kiran, Strong Alanna, Frank-Kamenetsky Maria, Lee Noemi E, Ahfeldt Tim, Sachs Katherine V, Li Xiaoyu, Li Hui, Kuperwasser Nicolas, Ruda Vera M, Pirruccello James P, Muchmore Brian, Prokunina-Olsson Ludmila, Hall Jennifer L, Schadt Eric E, Morales Carlos R, Lund-Katz Sissel, Phillips Michael C, Wong Jamie, Cantley William, Racie Timothy, Ejebe Kenechi G, Orho-Melander Marju, Melander Olle, Koteliansky Victor, Fitzgerald Kevin, Krauss Ronald M, Cowan Chad A, Kathiresan Sekar, Rader Daniel J in Nature (2010).

[PMID: 20686566] PubMed


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.

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