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Verfasst von:Blattmann, Peter Nils [VerfasserIn]   i
 Schuberth, Christian [VerfasserIn]   i
 Pepperkok, Rainer [VerfasserIn]   i
 Runz, Heiko [VerfasserIn]   i
Titel:RNAi-based functional profiling of loci from blood lipid genome-wide association studies identifies genes with cholesterol-regulatory function
Verf.angabe:Peter Blattmann, Christian Schuberth, Rainer Pepperkok, Heiko Runz
E-Jahr:2013
Jahr:February 28, 2020
Teil:volume:9
 year:2013
 number:2
Fussnoten:Gesehen am 27.11.2020
Titel Quelle:Enthalten in: Public Library of SciencePLoS Genetics
Ort Quelle:San Francisco, Calif. : Public Library of Science, 2005
Jahr Quelle:2013
Band/Heft Quelle:(2020,2) Artikel-Nummer e1003338, 13 Seiten
ISSN Quelle:1553-7404
Abstract:Genome-wide association studies (GWAS) are powerful tools to unravel genomic loci associated with common traits and complex human disease. However, GWAS only rarely reveal information on the exact genetic elements and pathogenic events underlying an association. In order to extract functional information from genomic data, strategies for systematic follow-up studies on a phenotypic level are required. Here we address these limitations by applying RNA interference (RNAi) to analyze 133 candidate genes within 56 loci identified by GWAS as associated with blood lipid levels, coronary artery disease, and/or myocardial infarction for a function in regulating cholesterol levels in cells. Knockdown of a surprisingly high number (41%) of trait-associated genes affected low-density lipoprotein (LDL) internalization and/or cellular levels of free cholesterol. Our data further show that individual GWAS loci may contain more than one gene with cholesterol-regulatory functions. Using a set of secondary assays we demonstrate for a number of genes without previously known lipid-regulatory roles (e.g. CXCL12, FAM174A, PAFAH1B1, SEZ6L, TBL2, WDR12) that knockdown correlates with altered LDL-receptor levels and/or that overexpression as GFP-tagged fusion proteins inversely modifies cellular cholesterol levels. By providing strong evidence for disease-relevant functions of lipid trait-associated genes, our study demonstrates that quantitative, cell-based RNAi is a scalable strategy for a systematic, unbiased detection of functional effectors within GWAS loci.
DOI:doi:10.1371/journal.pgen.1003338
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext ; Verlag: https://doi.org/10.1371/journal.pgen.1003338
 Volltext: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003338
 DOI: https://doi.org/10.1371/journal.pgen.1003338
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:Cholesterol
 Genetic loci
 Genome-wide association studies
 Lipid analysis
 Lipids
 RNA interference
 Small interfering RNA
 Transfection
K10plus-PPN:1741300878
Verknüpfungen:→ Zeitschrift

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