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dc.contributor.authorMehdi, Ahmed M
dc.contributor.authorHamilton-Williams, Emma E
dc.contributor.authorCristino, Alexandre
dc.contributor.authorZiegler, Anette
dc.contributor.authorBonifacio, Ezio
dc.contributor.authorLe Cao, Kim-Anh
dc.contributor.authorHarris, Mark
dc.contributor.authorThomas, Ranjeny
dc.date.accessioned2020-02-05T23:54:13Z
dc.date.available2020-02-05T23:54:13Z
dc.date.issued2018
dc.identifier.issn2379-3708
dc.identifier.doi10.1172/jci.insight.98212
dc.identifier.urihttp://hdl.handle.net/10072/391116
dc.description.abstractAutoimmune-mediated destruction of pancreatic islet β cells results in type 1 diabetes (T1D). Serum islet autoantibodies usually develop in genetically susceptible individuals in early childhood before T1D onset, with multiple islet autoantibodies predicting diabetes development. However, most at-risk children remain islet-antibody negative, and no test currently identifies those likely to seroconvert. We sought a genomic signature predicting seroconversion risk by integrating longitudinal peripheral blood gene expression profiles collected in high-risk children included in the BABYDIET and DIPP cohorts, of whom 50 seroconverted. Subjects were followed for 10 years to determine time of seroconversion. Any cohort effect and the time of seroconversion were corrected to uncover genes differentially expressed (DE) in seroconverting children. Gene expression signatures associated with seroconversion were evident during the first year of life, with 67 DE genes identified in seroconverting children relative to those remaining antibody negative. These genes contribute to T cell–, DC-, and B cell–related immune responses. Near-birth expression of ADCY9, PTCH1, MEX3B, IL15RA, ZNF714, TENM1, and PLEKHA5, along with HLA risk score predicted seroconversion (AUC 0.85). The ubiquitin-proteasome pathway linked DE genes and T1D susceptibility genes. Therefore, a gene expression signature in infancy predicts risk of seroconversion. Ubiquitination may play a mechanistic role in diabetes progression.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Society for Clinical Investigation
dc.publisher.placeUnited States
dc.relation.ispartofpagefrome98212: 1
dc.relation.ispartofpagetoe98212: 13
dc.relation.ispartofissue5
dc.relation.ispartofjournalJCI Insight
dc.relation.ispartofvolume3
dc.subject.fieldofresearchClinical sciences
dc.subject.fieldofresearchcode3202
dc.titleA peripheral blood transcriptomic signature predicts autoantibody development in infants at risk of type 1 diabetes
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationMehdi, AM; Hamilton-Williams, EE; Cristino, A; Ziegler, A; Bonifacio, E; Le Cao, K-A; Harris, M; Thomas, R, A peripheral blood transcriptomic signature predicts autoantibody development in infants at risk of type 1 diabetes, JCI Insight, 2018, 3 (5), pp. e98212: 1-e98212: 13
dc.date.updated2020-02-04T06:12:08Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2018 American Society for Clinical Investigation (ASCI). The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
gro.hasfulltextFull Text
gro.griffith.authorCristino, Alex


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