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dc.contributor.authorSteri, Men
dc.contributor.authorOrrù, Ven
dc.contributor.authorIdda, MLen
dc.contributor.authorPitzalis, Men
dc.contributor.authorPala, Men
dc.contributor.authorZara, Ien
dc.contributor.authorSidore, Cen
dc.contributor.authorFaà, Ven
dc.contributor.authorFloris, Men
dc.contributor.authorDeiana, Men
dc.contributor.authorAsunis, Ien
dc.contributor.authorPorcu, Een
dc.contributor.authorMulas, Aen
dc.contributor.authorPiras, MGen
dc.contributor.authorLobina, Men
dc.contributor.authorLai, Sen
dc.contributor.authorMarongiu, Men
dc.contributor.authorSerra, Ven
dc.contributor.authorMarongiu, Men
dc.contributor.authorSole, Gen
dc.contributor.authorBusonero, Fen
dc.contributor.authorMaschio, Aen
dc.contributor.authorCusano, Ren
dc.contributor.authorCuccuru, Gen
dc.contributor.authorDeidda, Fen
dc.contributor.authorPoddie, Fen
dc.contributor.authorFarina, Gen
dc.contributor.authorDei, Men
dc.contributor.authorVirdis, Fen
dc.contributor.authorOlla, Sen
dc.contributor.authorSatta, MAen
dc.contributor.authorPani, Men
dc.contributor.authorDelitala, Aen
dc.contributor.authorCocco, Een
dc.contributor.authorFrau, Jen
dc.contributor.authorCoghe, Gen
dc.contributor.authorLorefice, Len
dc.contributor.authorFenu, Gen
dc.contributor.authorFerrigno, Pen
dc.contributor.authorBan, Mariaen
dc.contributor.authorBarizzone, Nen
dc.contributor.authorLeone, Men
dc.contributor.authorGuerini, FRen
dc.contributor.authorPiga, Men
dc.contributor.authorFirinu, Den
dc.contributor.authorKockum, Ien
dc.contributor.authorLima Bomfim, Ien
dc.contributor.authorOlsson, Ten
dc.contributor.authorAlfredsson, Len
dc.contributor.authorSuarez, Aen
dc.contributor.authorCarreira, PEen
dc.contributor.authorCastillo-Palma, MJen
dc.contributor.authorMarcus, JHen
dc.contributor.authorCongia, Men
dc.contributor.authorAngius, Aen
dc.contributor.authorMelis, Men
dc.contributor.authorGonzalez, Aen
dc.contributor.authorAlarcón Riquelme, MEen
dc.contributor.authorda Silva, BMen
dc.contributor.authorMarchini, Men
dc.contributor.authorDanieli, MGen
dc.contributor.authorDel Giacco, Sen
dc.contributor.authorMathieu, Aen
dc.contributor.authorPani, Aen
dc.contributor.authorMontgomery, SBen
dc.contributor.authorRosati, Gen
dc.contributor.authorHillert, Jen
dc.contributor.authorSawcer, Stephenen
dc.contributor.authorD'Alfonso, Sen
dc.contributor.authorTodd, JAen
dc.contributor.authorNovembre, Jen
dc.contributor.authorAbecasis, GRen
dc.contributor.authorWhalen, MBen
dc.contributor.authorMarrosu, MGen
dc.contributor.authorMeloni, Aen
dc.contributor.authorSanna, Sen
dc.contributor.authorGorospe, Men
dc.contributor.authorSchlessinger, Den
dc.contributor.authorFiorillo, Een
dc.contributor.authorZoledziewska, Men
dc.contributor.authorCucca, Fen
dc.date.accessioned2017-06-27T15:30:57Z
dc.date.available2017-06-27T15:30:57Z
dc.date.issued2017-04-27en
dc.identifier.issn0028-4793
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/265029
dc.description.abstract$\textbf{BACKGROUND}$: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. $\textbf{METHODS}$: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. $\textbf{RESULTS}$: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. $\textbf{CONCLUSIONS}$: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).
dc.description.sponsorshipSupported by grants (2011/R/13 and 2015/R/09, to Dr. Cucca) from the Italian Foundation for Multiple Sclerosis; contracts (N01-AG-1-2109 and HHSN271201100005C, to Dr. Cucca) from the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH); a grant (FaReBio2011 “Farmaci e Reti Biotecnologiche di Qualità,” to Dr. Cucca) from the Italian Ministry of Economy and Finance; a grant (633964, to Dr. Cucca) from the Horizon 2020 Research and Innovation Program of the European Union; a grant (U1301.2015/AI.1157.BE Prat. 2015-1651, to Dr. Cucca) from Fondazione di Sardegna; grants (“Centro per la ricerca di nuovi farmaci per malattie rare, trascurate e della povertà” and “Progetto collezione di composti chimici ed attività di screening,” to Dr. Cucca) from Ministero dell’Istruzione, dell’Università e della Ricerca; grants (HG005581, HG005552, HG006513, and HG007022, to Dr. Abecasis) from the National Human Genome Research Institute; a grant (9-2011-253, to Dr. Todd) from JDRF; a grant (091157, to Dr. Todd) from the Wellcome Trust; a grant (to Dr. Todd) from the National Institute for Health Research (NIHR); and the NIHR Cambridge Biomedical Research Centre. Dr. Idda was a recipient of a Master and Back fellowship from the Autonomous Region of Sardinia.
dc.languageengen
dc.language.isoenen
dc.publisherMassachusetts Medical Society
dc.subjectautoimmunityen
dc.subjectB-Cell Activating Factoren
dc.subjectcase-control studiesen
dc.subjectgene Expressionen
dc.subjectGenome-Wide Association Studyen
dc.subjecthumansen
dc.subjectINDEL Mutationen
dc.subjectItalyen
dc.subjectLupus Erythematosus, Systemicen
dc.subjectMicroRNAsen
dc.subjectmultiple sclerosisen
dc.subjectphenotypeen
dc.subjectpolymorphism, single nucleotideen
dc.subjectrisken
dc.subjectsequence analysis, RNAen
dc.subjecttranscription, geneticen
dc.titleOverexpression of the Cytokine BAFF and Autoimmunity Risken
dc.typeArticle
prism.endingPage1626
prism.issueIdentifier17en
prism.publicationDate2017en
prism.publicationNameThe New England Journal of Medicineen
prism.startingPage1615
prism.volume376en
dc.identifier.doi10.17863/CAM.10946
dcterms.dateAccepted2017-01-17en
rioxxterms.versionofrecord10.1056/NEJMoa1610528en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-04-27en
dc.contributor.orcidSawcer, Stephen [0000-0001-7685-0974]
dc.identifier.eissn1533-4406
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (091157/Z/10/B)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Societal Challenges (633964)
rioxxterms.freetoread.startdate2017-10-27


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