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Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4

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dc.audienceComunidad Rosaristaspa
dc.creatorManku, Harinder
dc.creatorLangefeld, Carl D.
dc.creatorGuerra, Sandra G.
dc.creatorMalik, Talat H.
dc.creatorAlarcón-Riquelme, Marta E.
dc.creatorAnaya, Juan-Manuel
dc.creatorBae, Sang-Cheol
dc.creatorBoackle, Susan
dc.creatorBrown, Elizabeth E.
dc.creatorCriswell, Lindsey A.
dc.creatorFreedman, Barry I.
dc.creatorGaffney, Patrick M.
dc.creatorGregersen, Peter A.
dc.creatorGuthridge, Joel M.
dc.creatorHan, Sang-Hoon
dc.creatorHarley, John B.
dc.creatorJacob, Chaim O.
dc.creatorJames, Judith A.
dc.creatorKamen, Diane L.
dc.creatorKaufman, Kenneth M.
dc.creatorKelly, Jennifer A.
dc.creatorMartin, Javier
dc.creatorMerrill, Joan T.
dc.creatorMoser, Kathy L.
dc.creatorNiewold, Timothy B.
dc.creatorPark, So-Yeon
dc.creatorPons-Estel, Bernardo A.
dc.creatorSawalha, Amr H.
dc.creatorScofield, Robert H.
dc.creatorShen, Nan
dc.creatorStevens, Anne M.
dc.creatorSun, Celi
dc.creatorGilkeson, Gary S.
dc.creatorEdberg, Jeffrey C.
dc.creatorKimberly, Robert P.
dc.creatorNath, Swapan K.
dc.creatorTsao, Betty P.
dc.creatorVyse, Timothy J.
dc.creator.googleManku, Harinder
dc.creator.googleLangefeld, Carl D.
dc.creator.googleGuerra, Sandra G.
dc.creator.googleMalik, Talat H.
dc.creator.googleAlarcon-Riquelme, Marta
dc.creator.googleAnaya, Juan-Manuel
dc.creator.googleBae, Sang-Cheol
dc.creator.googleBoackle, Susan A.
dc.creator.googleBrown, Elizabeth E.
dc.creator.googleCriswell, Lindsey A.
dc.creator.googleFreedman, Barry I.
dc.creator.googleGaffney, Patrick M.
dc.creator.googleGregersen, Peter A.
dc.creator.googleGuthridge, Joel M.
dc.creator.googleHan, Sang-Hoon
dc.creator.googleHarley, John B.
dc.creator.googleJacob, Chaim O.
dc.creator.googleJames, Judith A.
dc.creator.googleKamen, Diane L.
dc.creator.googleKaufman, Kenneth M.
dc.creator.googleKelly, Jennifer A.
dc.creator.googleMartin, Javier
dc.creator.googleMerrill, Joan T.
dc.creator.googleMoser, Kathy L.
dc.creator.googleNiewold, Timothy B.
dc.creator.googlePark, So-Yeon
dc.creator.googlePons-Estel, Bernardo A.
dc.creator.googleSawalha, Arm H.
dc.creator.googleScofield, R. Hal
dc.creator.googleShen, Nan
dc.creator.googleStevens, Anne M.
dc.creator.googleSun, Celi
dc.creator.googleGilkeson, Gary S.
dc.creator.googleEdberg, Jeff C.
dc.creator.googleKimberly, Robert P.
dc.creator.googleNath, Swapan K.
dc.creator.googleTsao, Betty P.
dc.creator.googleVyse, Tim J.
dc.date.accessioned2014-08-13T16:06:10Z
dc.date.available2014-08-13T16:06:10Z
dc.date.created2013-07
dc.date.issued2013
dc.description.abstractWe previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10-34, OR = 1.43[1.26-1.60]) and rs1234317-T (P = 1.16×10-28, OR = 1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait. © 2013 Manku et al.eng
dc.format.mediumRecurso electrónicospa
dc.format.mimetypeapplication/pdf
dc.format.tipoDocumentospa
dc.identifier.doihttps://doi.org/10.1371/journal.pgen.1003554
dc.identifier.issn1553-7390
dc.identifier.urihttp://repository.urosario.edu.co/handle/10336/8829
dc.language.isoeng
dc.publisherUniversidad del Rosariospa
dc.relation.citationIssueNo. 7
dc.relation.citationTitlePLoS Genetics
dc.relation.citationVolumeVol. 9
dc.relation.ispartofPLoS Genetics ISSN: 15537390 V. 9 N. 7 Jul, 2013spa
dc.relation.urihttp://www.plosgenetics.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pgen.1003554&representation=PDF
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto completo)spa
dc.rights.licenciaEL AUTOR, manifiesta que la obra objeto de la presente autorización es original y la realizó sin violar o usurpar derechos de autor de terceros, por lo tanto la obra es de exclusiva autoría y tiene la titularidad sobre la misma.spa
dc.source.instnameinstname:Universidad del Rosariospa
dc.source.reponamereponame:Repositorio Institucional EdocURspa
dc.subject.ddcEvolución & genética
dc.subject.decsAnticuerposspa
dc.subject.decsAlelosspa
dc.subject.decsGenéticaspa
dc.subject.decsInmunologíaspa
dc.subject.keywordAutoantibodyeng
dc.subject.keywordOX40 ligandeng
dc.subject.keywordTranscription factor RelAeng
dc.subject.keywordAfrican Americaneng
dc.subject.keywordAlleleeng
dc.subject.keywordAmerican Indianeng
dc.subject.keywordAntibody productioneng
dc.subject.keywordCell isolationeng
dc.titleTrans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4spa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/acceptedVersion
dc.type.spaArtículospa
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