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

Musunuru, Kiran; Strong, Alanna; Frank-Kamenetsky, Maria; Lee, Noemi E.; Ahfeldt, Tim; Sachs, Katherine V.; Li, Xiaoyu; Li, Hui; Kuperwasser, Nicolas and Ruda, Vera M., et al. (2010) In Nature 466(7307). p.2-714
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... (More)
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. (Less)
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@article{0c20e8b5-d529-41b4-be11-bcebf87162da,
  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.},
  author       = {Musunuru, Kiran and Strong, Alanna and Frank-Kamenetsky, Maria and Lee, Noemi E. and Ahfeldt, Tim and Sachs, Katherine V. and Li, Xiaoyu and Li, Hui and Kuperwasser, Nicolas and Ruda, Vera M. and Pirruccello, James P. and Muchmore, Brian and Prokunina-Olsson, Ludmila and Hall, Jennifer L. and Schadt, Eric E. and Morales, Carlos R. and Lund-Katz, Sissel and Phillips, Michael C. and Wong, Jamie and Cantley, William and Racie, Timothy and Ejebe, Kenechi G. and Orho-Melander, Marju and Melander, Olle and Koteliansky, Victor and Fitzgerald, Kevin and Krauss, Ronald M. and Cowan, Chad A. and Kathiresan, Sekar and Rader, Daniel J.},
  issn         = {0028-0836},
  language     = {eng},
  number       = {7307},
  pages        = {2--714},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus},
  url          = {http://dx.doi.org/10.1038/nature09266},
  volume       = {466},
  year         = {2010},
}