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dc.contributor.authorNAKAGOME, SHIGEKIen
dc.date.accessioned2016-09-29T12:48:34Z
dc.date.available2016-09-29T12:48:34Z
dc.date.issued2016en
dc.date.submitted2016en
dc.identifier.citationKariuki SN, Maranville JC, Baxter SS, Jeong C, Nakagome S, Hrusch CL, Witonsky DB, Sperling AI, Di Rienzo A, Mapping Variation in Cellular and Transcriptional Response to 1,25-Dihydroxyvitamin D3 in Peripheral Blood Mononuclear Cells., PloS one, 11, 7, 2016, e0159779en
dc.identifier.issn1932-6203en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/77453
dc.descriptionPUBLISHEDen
dc.description.abstractThe active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is an important modulator of the immune system, inhibiting cellular proliferation and regulating transcription of immune response genes. In order to characterize the genetic basis of variation in the immunomodulatory effects of 1,25D, we mapped quantitative traits of 1,25D response at both the cellular and the transcriptional level. We carried out a genome-wide association scan of percent inhibition of cell proliferation (Imax) induced by 1,25D treatment of peripheral blood mononuclear cells from 88 healthy African-American individuals. Two genome-wide significant variants were identified: rs1893662 in a gene desert on chromosome 18 (p = 2.32 x 10−8) and rs6451692 on chromosome 5 (p = 2.55 x 10−8), which may influence the anti-proliferative activity of 1,25D by regulating the expression of nearby genes such as the chemokine gene, CCL28, and the translation initiation gene, PAIP1. We also identified 8 expression quantitative trait loci at a FDR<0.10 for transcriptional response to 1,25D treatment, which include the transcriptional regulator ets variant 3-like (ETV3L) and EH-domain containing 4 (EHD4). In addition, we identified response eQTLs in vitamin D receptor binding sites near genes differentially expressed in response to 1,25D, such as FERM Domain Containing 6 (FRMD6), which plays a critical role in regulating both cell proliferation and apoptosis. Combining information from the GWAS of Imax and the response eQTL mapping enabled identification of putative Imax-associated candidate genes such as PAIP1 and the transcriptional repressor gene ZNF649. Overall, the variants identified in this study are strong candidates for immune traits and diseases linked to vitamin D, such as multiple sclerosis.en
dc.description.sponsorshipThis work was supported in part by NIH grant (R01 GM101682) to ADR. SNK was supported by a Howard Hughes Medical Institute Gilliam Fellowship for Advanced Study. CJ was supported by a Samsung Scholarship for post-graduate overseas education of Korean nationals. This project was supported by the University of Chicago Comprehensive Cancer Center Support Grant (#P30 CA14599), with particular support from the Genomics Core Facility. The Center for Research Informatics is funded by the Biological Sciences Division at the University of Chicago with additional funding provided by the Institute for Translational Medicine, CTSA grant number UL1 TR000430 from the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.format.extente0159779en
dc.relation.ispartofseriesPloS oneen
dc.relation.ispartofseries11en
dc.relation.ispartofseries7en
dc.rightsYen
dc.titleMapping Variation in Cellular and Transcriptional Response to 1,25-Dihydroxyvitamin D3 in Peripheral Blood Mononuclear Cells.en
dc.typeJournal Articleen
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/nakagomsen
dc.identifier.rssinternalid128174en
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0159779en
dc.rights.ecaccessrightsopenAccess
dc.identifier.orcid_id0000-0001-9613-975Xen


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