dc.contributor.author | Fendler, W | |
dc.contributor.author | Madzio, J | |
dc.contributor.author | Kozinski, K | |
dc.contributor.author | Patel, K | |
dc.contributor.author | Janikiewicz, J | |
dc.contributor.author | Szopa, M | |
dc.contributor.author | Tracz, A | |
dc.contributor.author | Borowiec, M | |
dc.contributor.author | Jarosz-Chobot, P | |
dc.contributor.author | Mysliwiec, M | |
dc.contributor.author | Szadkowska, A | |
dc.contributor.author | Hattersley, AT | |
dc.contributor.author | Ellard, S | |
dc.contributor.author | Malecki, MT | |
dc.contributor.author | Dobrzyn, A | |
dc.contributor.author | Mlynarski, W | |
dc.date.accessioned | 2016-06-21T09:23:24Z | |
dc.date.issued | 2016-04-08 | |
dc.description.abstract | AIMS/HYPOTHESIS: We aimed to identify microRNAs (miRNAs) under transcriptional control of the HNF1β transcription factor, and investigate whether its effect manifests in serum. METHODS: The Polish cohort (N = 60) consisted of 11 patients with HNF1B-MODY, 17 with HNF1A-MODY, 13 with GCK-MODY, an HbA1c-matched type 1 diabetic group (n = 9) and ten healthy controls. Replication was performed in 61 clinically-matched British patients mirroring the groups in the Polish cohort. The Polish cohort underwent miRNA serum level profiling with quantitative real-time PCR (qPCR) arrays to identify differentially expressed miRNAs. Validation was performed using qPCR. To determine whether serum content reflects alterations at a cellular level, we quantified miRNA levels in a human hepatocyte cell line (HepG2) with small interfering RNA knockdowns of HNF1α or HNF1β. RESULTS: Significant differences (adjusted p < 0.05) were noted for 11 miRNAs. Five of them differed between HNF1A-MODY and HNF1B-MODY, and, amongst those, four (miR-24, miR-27b, miR-223 and miR-199a) showed HNF1B-MODY-specific expression levels in the replication group. In all four cases the miRNA expression level was lower in HNF1B-MODY than in all other tested groups. Areas under the receiver operating characteristic curves ranged from 0.79 to 0.86, with sensitivity and specificity reaching 91.7% (miR-24) and 82.1% (miR-199a), respectively. The cellular expression pattern of miRNA was consistent with serum levels, as all were significantly higher in HNF1α- than in HNF1β-deficient HepG2 cells. CONCLUSIONS/INTERPRETATION: We have shown that expression of specific miRNAs depends on HNF1β function. The impact of HNF1β deficiency was evidenced at serum level, making HNF1β-dependent miRNAs potentially applicable in the diagnosis of HNF1B-MODY. | en_GB |
dc.description.sponsorship | The project was funded by the National Science Centre of Poland (no. 2012/05/E/NZ5/02130), a research grant from Diabetes Poland, and the INTER programme of the Foundation for Polish Science (29/UD/SKILLS/2015). JM is supported by funds from the National Science Centre for Research and Development (grant number 635/L-5/2013). MS received financial support from the Iuventus Plus programme of the Ministry of Science and Higher Education (no. IP2011 054571). MB was supported by the National Science Centre (grant number 2013/09/B/NZ5/00779). SE and ATH are Wellcome Trust senior investigators. AD, KK and JJ were supported by a Polish Science Foundation grant (TEAM/2010-5/2) and National Science Centre grants (2011/03/B/NZ4/03055 and 2011/03/B/NZ3/00693). | en_GB |
dc.identifier.citation | Diabetologia, 2016, Vol. 59, Issue 7, pp. 1463 - 1473 | en_GB |
dc.identifier.doi | 10.1007/s00125-016-3945-0 | |
dc.identifier.uri | http://hdl.handle.net/10871/22193 | |
dc.language.iso | en | en_GB |
dc.publisher | Springer Verlag | en_GB |
dc.relation.url | http://www.ncbi.nlm.nih.gov/pubmed/27059371 | en_GB |
dc.rights | This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record. | en_GB |
dc.subject | HNF | en_GB |
dc.subject | MODY | en_GB |
dc.subject | Monogenic diabetes | en_GB |
dc.subject | Transcription factors | en_GB |
dc.subject | microRNA | en_GB |
dc.title | Differential regulation of serum microRNA expression by HNF1β and HNF1α transcription factors. | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2016-06-21T09:23:24Z | |
dc.identifier.issn | 0012-186X | |
exeter.place-of-publication | Germany | |
dc.identifier.journal | Diabetologia | en_GB |