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dc.contributor.authorSingh PK
dc.contributor.authorvan den Berg PR
dc.contributor.authorLong MD
dc.contributor.authorVreugdenhil A
dc.contributor.authorGrieshober L
dc.contributor.authorOchs-Balcom HM
dc.contributor.authorWang J
dc.contributor.authorDelcambre S
dc.contributor.authorHeikkinen S
dc.contributor.authorCarlberg C
dc.contributor.authorCampbell MJ
dc.contributor.authorSucheston-Campbell LE
dc.date.accessioned2017-05-22T11:25:20Z
dc.date.available2017-05-22T11:25:20Z
dc.date.issued2017
dc.identifier10.1186/s12864-017-3481-4fi_FI
dc.identifier.issn1471-2164
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/2599
dc.descriptionArticle
dc.description.abstractBackground The nuclear hormone receptor superfamily acts as a genomic sensor of diverse signals. Their actions are often intertwined with other transcription factors. Nuclear hormone receptors are targets for many therapeutic drugs, and include the vitamin D receptor (VDR). VDR signaling is pleotropic, being implicated in calcaemic function, antibacterial actions, growth control, immunomodulation and anti-cancer actions. Specifically, we hypothesized that the biologically significant relationships between the VDR transcriptome and phenotype-associated biology could be discovered by integrating the known VDR transcription factor binding sites and all published trait- and disease-associated SNPs. By integrating VDR genome-wide binding data (ChIP-seq) with the National Human Genome Research Institute (NHGRI) GWAS catalog of SNPs we would see where and which target gene interactions and pathways are impacted by inherited genetic variation in VDR binding sites, indicating which of VDR’s multiple functions are most biologically significant. Results To examine how genetic variation impacts VDR function we overlapped 23,409 VDR genomic binding peaks from six VDR ChIP-seq datasets with 191,482 SNPs, derived from GWAS-significant SNPs (Lead SNPs) and their correlated variants (r 2 > 0.8) from HapMap3 and the 1000 genomes project. In total, 574 SNPs (71 Lead and 503 SNPs in linkage disequilibrium with Lead SNPs) were present at VDR binding loci and associated with 211 phenotypes. For each phenotype a hypergeometric test was used to determine if SNPs were enriched at VDR binding sites. Bonferroni correction for multiple testing across the 211 phenotypes yielded 42 SNPs that were either disease- or phenotype-associated with seven predominately immune related including self-reported allergy; esophageal cancer was the only cancer phenotype. Motif analyses revealed that only two of these 42 SNPs reside within a canonical VDR binding site (DR3 motif), and that 1/3 of the 42 SNPs significantly impacted binding and gene regulation by other transcription factors, including NF-κB. This suggests a plausible link for the potential cross-talk between VDR and NF-κB. Conclusions These analyses showed that VDR peaks are enriched for SNPs associated with immune phenotypes suggesting that VDR immunomodulatory functions are amongst its most important actions. The enrichment of genetic variation in non-DR3 motifs suggests a significant role for the VDR to bind in multimeric complexes containing other transcription factors that are the primary DNA binding component. Our work provides a framework for the combination of ChIP-seq and GWAS findings to provide insight into the underlying phenotype-associated biology of a given transcription factor.fi_FI
dc.language.isoENfi_FI
dc.publisherBioMed Central Ltdfi_FI
dc.relation.ispartofseriesBMC Genomics
dc.relation.urihttps://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-017-3481-4fi_FI
dc.rightsCC BY http://creativecommons.org/licenses/by/4.0/
dc.subjectVDRfi_FI
dc.subjectGWASfi_FI
dc.subjectSNPfi_FI
dc.subjectImmune functionfi_FI
dc.subjectChIP-seqfi_FI
dc.subjectNF-κBfi_FI
dc.subjectLinkage disequilibriumfi_FI
dc.subjectNuclear receptor superfamilyfi_FI
dc.subjectCistromefi_FI
dc.subjectDR3 motiffi_FI
dc.titleIntegration of VDR genome wide binding and GWAS genetic variation data reveals co-occurrence of VDR and NF-kappaB binding that is linked to immune phenotypesfi_FI
dc.typehttp://purl.org/eprint/type/JournalArticle
dc.description.versionPublisher's pdffi_FI
dc.contributor.departmentSchool of Medicine / Biomedicine
uef.solecris.id47041279
eprint.statushttp://purl.org/eprint/status/PeerReviewedfi_FI
dc.type.publicationinfo:eu-repo/semantics/article
dc.rights.accessrights© The Authors
dc.relation.doi10.1186/s12864-017-3481-4
dc.description.reviewstatushttp://purl.org/eprint/status/PeerReviewed
dc.relation.articlenumber132
dc.relation.issn1471-2164
dc.relation.issue1
dc.relation.volume18
dc.rights.accesslevelopenAccess


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