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dc.contributor.authorChen, Zhifenen
dc.contributor.authorYu, Haojieen
dc.contributor.authorShi, Xuen
dc.contributor.authorWarren, Curtis Ren
dc.contributor.authorLotta, Luca Aen
dc.contributor.authorFriesen, Maxen
dc.contributor.authorMeissner, Torsten Ben
dc.contributor.authorLangenberg, Claudiaen
dc.contributor.authorWabitsch, Martinen
dc.contributor.authorWareham, Nicholasen
dc.contributor.authorBenson, Mark Den
dc.contributor.authorGerszten, Rob Een
dc.contributor.authorCowan, Chad Aen
dc.date.accessioned2019-11-26T00:30:43Z
dc.date.available2019-11-26T00:30:43Z
dc.date.issued2020-01en
dc.identifier.issn0009-7330
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/299231
dc.description.abstractRationale: Genome-wide association studies (GWAS) have identified genetic loci associated with insulin resistance (IR) but pinpointing the causal genes of a risk locus has been challenging. Objective: To identify candidate causal genes for IR, we screened regional and biologically plausible genes (16 in total) near the top ten IR-loci in risk-relevant cell types, namely preadipocytes and adipocytes. Methods and Results: We generated 16 human Simpson-Golabi-Behmel syndrome preadipocyte knockout lines (SGBS-KO) by lentivirus-mediated CRISPR/Cas9 system. We evaluated each gene knockout by screening IR-relevant phenotypes in the three insulin-sensitizing mechanisms, including adipogenesis, lipid metabolism and insulin signaling. We performed genetic analyses to evaluate whether candidate genes prioritized by our in vitro studies were eQTL genes in human subcutaneous adipose tissue, and were associated with risk of IR, type 2 diabetes (T2D) and cardiovascular diseases (CVD). We further validated the functions of three new adipose IR genes by phenotypic rescue in the SGBS-KO cell lines. Results: Twelve genes, PPARG, IRS-1, FST, PEPD, PDGFC, MAP3K1, GRB14, ARL15, ANKRD55, RSPO3, COBLL1 and LYPLAL1, showed diverse phenotypes in the three insulin-sensitizing mechanisms, and the first seven of these genes could affect all the three mechanisms. Five of six eQTL genes are among the top candidate causal genes and the abnormal expression levels of these genes (IRS-1, GRB14, FST, PEPD and PDGFC) in human SAT could be associated with increased risk of IR, T2D and CVD. Phenotypic rescue of FST, PEPD and PDGFC in the SGBS-KO lines confirmed their function in adipose IR. Conclusions: Twelve genes showed diverse phenotypes indicating differential roles in insulin sensitization, suggesting mechanisms bridging the association of their genomic loci with IR. We prioritized PPARG, IRS-1, GRB14, MAP3K1, FST, PEPD and PDGFC as top candidate genes. Our work points to novel roles for FST, PEPD and PDGFC in adipose tissue, with consequences for cardiometabolic diseases.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.rightsAll rights reserved
dc.rights.uri
dc.subjectCell Lineen
dc.subjectAdipocytesen
dc.subjectHumansen
dc.subjectInsulin Resistanceen
dc.subjectDipeptidasesen
dc.subjectMAP Kinase Kinase Kinase 1en
dc.subjectPlatelet-Derived Growth Factoren
dc.subjectAdaptor Proteins, Signal Transducingen
dc.subjectFollistatinen
dc.subjectPPAR gammaen
dc.subjectLymphokinesen
dc.subjectQuantitative Trait Locien
dc.subjectGenome-Wide Association Studyen
dc.subjectInsulin Receptor Substrate Proteinsen
dc.subjectLoss of Function Mutationen
dc.titleFunctional Screening of Candidate Causal Genes for Insulin Resistance in Human Preadipocytes and Adipocytes.en
dc.typeArticle
prism.endingPage346
prism.issueIdentifier3en
prism.publicationDate2020en
prism.publicationNameCirculation researchen
prism.startingPage330
prism.volume126en
dc.identifier.doi10.17863/CAM.46296
dcterms.dateAccepted2019-11-15en
rioxxterms.versionofrecord10.1161/circresaha.119.315246en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2020-01en
dc.contributor.orcidYu, Haojie [0000-0002-0559-0252]
dc.contributor.orcidLangenberg, Claudia [0000-0002-5017-7344]
dc.contributor.orcidWareham, Nicholas [0000-0003-1422-2993]
dc.identifier.eissn1524-4571
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_UU_12015/1)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
cam.orpheus.successThu Jan 30 10:35:17 GMT 2020 - Embargo updated*
rioxxterms.freetoread.startdate2020-05-19


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