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  • 1
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    From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-08-06
    Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062476/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062476/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- K99 HL098364/HL/NHLBI NIH HHS/ -- K99 HL098364-01/HL/NHLBI NIH HHS/ -- K99 HL098364-02/HL/NHLBI NIH HHS/ -- K99-HL098364/HL/NHLBI NIH HHS/ -- P01 HL059407/HL/NHLBI NIH HHS/ -- P01 HL059407-13/HL/NHLBI NIH HHS/ -- P01-HL059407/HL/NHLBI NIH HHS/ -- RC2 HL101864/HL/NHLBI NIH HHS/ -- RC2 HL101864-02/HL/NHLBI NIH HHS/ -- RC2-HL101864/HL/NHLBI NIH HHS/ -- T32 HL007954/HL/NHLBI NIH HHS/ -- T32 HL007954-10/HL/NHLBI NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL069757-09/HL/NHLBI NIH HHS/ -- U01-HL069757/HL/NHLBI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2010 Aug 5;466(7307):714-9. doi: 10.1038/nature09266.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20686566" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Vesicular ; Transport/biosynthesis/deficiency/genetics/*metabolism ; Animals ; Base Sequence ; Binding Sites ; CCAAT-Enhancer-Binding Proteins/metabolism ; Cells, Cultured ; Cholesterol, LDL/blood/*metabolism ; Chromosomes, Human, Pair 1/*genetics ; Cohort Studies ; Coronary Artery Disease/blood/genetics ; Europe/ethnology ; Gene Expression Regulation ; Gene Knockdown Techniques ; Genetic Predisposition to Disease/*genetics ; Genome-Wide Association Study ; Haplotypes/genetics ; Hepatocytes/metabolism/secretion ; Humans ; Lipids/blood ; Lipoproteins, VLDL/blood/secretion ; Liver/cytology/metabolism/secretion ; Mice ; Myocardial Infarction/blood/genetics ; Phenotype ; Polymorphism, Single Nucleotide/*genetics ; Transcription, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    A statin-dependent QTL for GATM expression is associated with statin-induced myopathy (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-09-03
    Description: Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933266/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933266/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mangravite, Lara M -- Engelhardt, Barbara E -- Medina, Marisa W -- Smith, Joshua D -- Brown, Christopher D -- Chasman, Daniel I -- Mecham, Brigham H -- Howie, Bryan -- Shim, Heejung -- Naidoo, Devesh -- Feng, QiPing -- Rieder, Mark J -- Chen, Yii-Der I -- Rotter, Jerome I -- Ridker, Paul M -- Hopewell, Jemma C -- Parish, Sarah -- Armitage, Jane -- Collins, Rory -- Wilke, Russell A -- Nickerson, Deborah A -- Stephens, Matthew -- Krauss, Ronald M -- HG002585/HG/NHGRI NIH HHS/ -- K99/R00HG006265/HG/NHGRI NIH HHS/ -- MC_U137686853/Medical Research Council/United Kingdom -- P30 DK063491/DK/NIDDK NIH HHS/ -- R00 HG006265/HG/NHGRI NIH HHS/ -- R01 HG002585/HG/NHGRI NIH HHS/ -- R01 HL104133/HL/NHLBI NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL69757/HL/NHLBI NIH HHS/ -- UL1 TR000124/TR/NCATS NIH HHS/ -- British Heart Foundation/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2013 Oct 17;502(7471):377-80. doi: 10.1038/nature12508. Epub 2013 Aug 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sage Bionetworks, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. lara.mangravite@sagebase.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23995691" target="_blank"〉PubMed〈/a〉
    Keywords: Amidinotransferases/deficiency/*genetics/metabolism ; Cell Line ; Cholesterol/deficiency/metabolism/pharmacology ; Gene Expression Regulation/*drug effects ; Gene Knockdown Techniques ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects/pharmacology ; Lymphocytes/cytology/drug effects/metabolism ; Muscular Diseases/*chemically induced/genetics/metabolism ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/*genetics ; Simvastatin/*adverse effects/pharmacology ; Sterol Regulatory Element Binding Proteins/metabolism ; Transcription, Genetic/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
    Location Call Number Expected Availability
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    PAPER CURRENT
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