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Mehdi, A.M.* ; Hamilton-Williams, E.E.* ; Cristino, A.* ; Ziegler, A.-G. ; Bonifacio, E.* ; Le Cao, K.A.* ; Harris, M.H.* ; Thomas, R.*

A peripheral blood transcriptomic signature predicts autoantibody development in infants at risk of type 1 diabetes.

JCI insight 3:e98212 (2018)
Verlagsversion DOI PMC
Open Access Gold
Autoimmune-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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Autoimmune Diseases ; Diabetes ; Endocrinology ; Immunology
ISSN (print) / ISBN 2379-3708
e-ISSN 2379-3708
Zeitschrift JCI insight
Quellenangaben Band: 3, Heft: 5, Seiten: , Artikelnummer: e98212 Supplement: ,
Verlag Clarivate
Verlagsort Ann Arbor, Michigan
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes Research Type 1 (IDF)