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Functional characterization of common BCL11B gene desert variants suggests a lymphocyte-mediated association of BCL11B with aortic stiffness.

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cam.issuedOnline2018-08-08
dc.contributor.authorMaskari, Raya Al
dc.contributor.authorHardege, Iris
dc.contributor.authorCleary, Sarah
dc.contributor.authorFigg, Nicki
dc.contributor.authorLi, Ye
dc.contributor.authorSiew, Keith
dc.contributor.authorKhir, Ashraf
dc.contributor.authorYu, Yong
dc.contributor.authorLiu, Pentao
dc.contributor.authorWilkinson, Ian
dc.contributor.authorO'Shaughnessy, Kevin
dc.contributor.authorYasmin
dc.contributor.orcidMaskari, Raya Al [0000-0002-1259-0197]
dc.contributor.orcidSiew, Keith [0000-0002-6502-5095]
dc.date.accessioned2018-09-05T12:49:25Z
dc.date.available2018-09-05T12:49:25Z
dc.date.issued2018-11
dc.description.abstractThe recent genome-wide analysis of carotid-femoral pulse wave velocity (PWV) identified a significant locus within the 14q32.2 gene desert. Gene regulatory elements for the transcriptional regulator B-cell CLL/lymphoma 11B (BCL11B) are within this locus and an attractive target for the gene association. We investigated the functional impact of these gene desert SNPs on BCL11B transcript in human aorta to characterize further its role in aortic stiffness. To do this, we used a large repository of aortic tissues (n = 185) from an organ transplant program and assessed ex vivo stiffness of the aortic rings. We tested association of three lead SNPs from the GWAS meta-analysis with ex vivo aortic stiffness and BCL11B aortic mRNA expression: rs1381289 and rs10782490 SNPs associated significantly with PWV and showed allele-specific differences in BCL11B mRNA. The risk alleles associated with lower BCL11B expression, suggesting a protective role for BCL11B. Despite strong association, we could not detect BCL11B protein in the human aorta. However, qPCR for CD markers showed that BCL11B transcript correlated strongly with markers for activated lymphocytes. Our data confirm the significance of the 14q32.2 region as a risk locus for aortic stiffness and an upstream regulator of BCL11B. The BCL11B transcript detected in the human aorta may reflect lymphocyte infiltration, suggesting that immune mechanisms contribute to the observed association of BCL11B with aortic stiffness.
dc.description.sponsorshipThis work was funded by a PhD studentship for RAM from the Omani Government, Rosetrees Trust (Ref. CM374), British Heart Foundation (FS12/8/29377) and the UK NIHR.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.26965
dc.identifier.eissn1476-5438
dc.identifier.issn1018-4813
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/279594
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41431-018-0226-z
dc.rightsAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAdult
dc.subjectAged
dc.subjectAnimals
dc.subjectAorta
dc.subjectBiomarkers
dc.subjectChromosomes, Human, Pair 14
dc.subjectFemale
dc.subjectHumans
dc.subjectLymphocyte Activation
dc.subjectMale
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMiddle Aged
dc.subjectPolymorphism, Single Nucleotide
dc.subjectPulse Wave Analysis
dc.subjectRNA, Messenger
dc.subjectRepressor Proteins
dc.subjectTumor Suppressor Proteins
dc.subjectVascular Stiffness
dc.titleFunctional characterization of common BCL11B gene desert variants suggests a lymphocyte-mediated association of BCL11B with aortic stiffness.
dc.typeArticle
dcterms.dateAccepted2018-07-03
prism.endingPage1657
prism.issueIdentifier11
prism.publicationDate2018
prism.publicationNameEur J Hum Genet
prism.startingPage1648
prism.volume26
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (None)
rioxxterms.licenseref.startdate2018-11
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41431-018-0226-z

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