Nasim Samandari1, Aashiq H Mirza1,2, Lotte B Nielsen1, Simranjeet Kaur1, Philip Hougaard3, Siri Fredheim1, Henrik B Mortensen1,4, Flemming Pociot5,6,7. 1. Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev and Gentofte Hospitals, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark. 2. Center for Non-coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark. 3. Department of Statistics, University of Southern Denmark, Odense, Denmark. 4. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 5. Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev and Gentofte Hospitals, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark. flemming.pociot.01@regionh.dk. 6. Center for Non-coding RNA in Technology and Health, University of Copenhagen, Copenhagen, Denmark. flemming.pociot.01@regionh.dk. 7. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. flemming.pociot.01@regionh.dk.
Abstract
AIMS/HYPOTHESIS: We aimed to identify circulating microRNA (miRNA) that predicts clinical progression in a cohort of 123 children with new-onset type 1 diabetes mellitus. METHODS: Plasma samples were prospectively obtained at 1, 3, 6, 12 and 60 months after diagnosis from a subset of 40 children from the Danish Remission Phase Cohort, and profiled for miRNAs. At the same time points, meal-stimulated C-peptide and HbA1c levels were measured and insulin-dose adjusted HbA1c (IDAA1c) calculated. miRNAs that at 3 months after diagnosis predicted residual beta cell function and glycaemic control in this subgroup were further validated in the remaining cohort (n = 83). Statistical analysis of miRNA prediction for disease progression was performed by multiple linear regression analysis adjusted for age and sex. RESULTS: In the discovery analysis, six miRNAs (hsa-miR-24-3p, hsa-miR-146a-5p, hsa-miR-194-5p, hsa-miR-197-3p, hsa-miR-301a-3p and hsa-miR-375) at 3 months correlated with residual beta cell function 6-12 months after diagnosis. Stimulated C-peptide at 12 months was predicted by hsa-miR-197-3p at 3 months (p = 0.034). A doubling of this miRNA level corresponded to a sixfold higher stimulated C-peptide level. In addition, a doubling of hsa-miR-24-3p and hsa-miR-146a-5p levels at 3 months corresponded to a 4.2% (p < 0.014) and 3.5% (p < 0.022) lower IDAA1c value at 12 months. Analysis of the remaining cohort confirmed the initial finding for hsa-miR-197-3p (p = 0.018). The target genes for the six miRNAs revealed significant enrichment for pathways related to gonadotropin-releasing hormone receptor and angiogenesis pathways. CONCLUSIONS/ INTERPRETATION: The miRNA hsa-miR-197-3p at 3 months was the strongest predictor of residual beta cell function 1 year after diagnosis in children with type 1 diabetes mellitus.
AIMS/HYPOTHESIS: We aimed to identify circulating microRNA (miRNA) that predicts clinical progression in a cohort of 123 children with new-onset type 1 diabetes mellitus. METHODS: Plasma samples were prospectively obtained at 1, 3, 6, 12 and 60 months after diagnosis from a subset of 40 children from the Danish Remission Phase Cohort, and profiled for miRNAs. At the same time points, meal-stimulated C-peptide and HbA1c levels were measured and insulin-dose adjusted HbA1c (IDAA1c) calculated. miRNAs that at 3 months after diagnosis predicted residual beta cell function and glycaemic control in this subgroup were further validated in the remaining cohort (n = 83). Statistical analysis of miRNA prediction for disease progression was performed by multiple linear regression analysis adjusted for age and sex. RESULTS: In the discovery analysis, six miRNAs (hsa-miR-24-3p, hsa-miR-146a-5p, hsa-miR-194-5p, hsa-miR-197-3p, hsa-miR-301a-3p and hsa-miR-375) at 3 months correlated with residual beta cell function 6-12 months after diagnosis. Stimulated C-peptide at 12 months was predicted by hsa-miR-197-3p at 3 months (p = 0.034). A doubling of this miRNA level corresponded to a sixfold higher stimulated C-peptide level. In addition, a doubling of hsa-miR-24-3p and hsa-miR-146a-5p levels at 3 months corresponded to a 4.2% (p < 0.014) and 3.5% (p < 0.022) lower IDAA1c value at 12 months. Analysis of the remaining cohort confirmed the initial finding for hsa-miR-197-3p (p = 0.018). The target genes for the six miRNAs revealed significant enrichment for pathways related to gonadotropin-releasing hormone receptor and angiogenesis pathways. CONCLUSIONS/ INTERPRETATION: The miRNA hsa-miR-197-3p at 3 months was the strongest predictor of residual beta cell function 1 year after diagnosis in children with type 1 diabetes mellitus.
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