MicroRNA expression and arterial function in type II diabetes mellitus
| dc.contributor.author | Goldfein, Batsheva | |
| dc.contributor.supervisor | Millen, Aletta | |
| dc.date.accessioned | 2024-11-27T11:08:28Z | |
| dc.date.available | 2024-11-27T11:08:28Z | |
| dc.date.issued | 2024 | |
| dc.description | A dissertation submitted in fulfillment of the requirements for the degree of Master of Science in Medicine June 2024 to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2024 | |
| dc.description.abstract | Background. Type II diabetes mellitus (T2DM) is a major health concern which significantly contributes to the global cardiovascular disease (CVD) burden. Arterial dysfunction is considered a subclinical marker of CVD and is associated with an increased risk of cardiovascular events. However, treatment outcomes for T2DM patients remain suboptimal, mainly due to a poor understanding and the lack of an early marker for the identification of subclinical CVD. Recently, microRNAs (miRNA), small, non-coding RNA molecules that regulate major signalling pathways through post-transcriptional modification, have been identified as possible epigenetic regulators in the development of many diseases. MiR-146a-5p, in particular, has received considerable attention as a biomarker associated with several disease states including inflammation, T2DM and CVD. However, studies surrounding the role of miR- 146a-5p in arterial function and subclinical CVD risk in diabetic populations have yielded contradictory results. Therefore, the aim of this study was to determine the role of miR-146a-5p expression in the development of arterial dysfunction in patients with T2DM. Methods. This case control study (n=118) included participants with a previous diagnosis of insulin resistance or T2DM (n=67), and a non-DM control group (n=51). Demographic characteristics and CVD risk factors were assessed using standard approaches. Arterial function was measured using applanation tonometry and SphygmoCor software. From the recorded radial and aortic waveforms, central systolic (cSBP) and pulse pressure (cPP), augmentation pressure (AP) and the forward (FWP) and reflected wave pressure (RWP) were derived using a generalised transfer function. The carotid-femoral pulse wave velocity (PWV) was measured as a marker of arterial stiffness. Using a fasting blood sample, serum concentrations of tumour necrosis factor α (TNFα) and matrix metalloproteinase 1 (MMP1) were quantified by ELISA. Real time quantitative PCR was used to determine the relative expression of miR-146a-5p using the comparative CT method relative to an endogenous control miRNA, miR-16-5p. Differences in anthropometric variables, miRNA expression and arterial function between the two groups were determined using unpaired t-tests or Mann Whitney U tests, as appropriate. Associations between miR-146a-5p expression and arterial function were determined using Pearson’s correlations. Participants were further stratified according to CVD risk using the Framingham risk score (FRS), and the associations with miRNA expression analysed using multivariate linear regression. Results. Participants with DM had significantly higher body mass index (p=0.002), triglyceride levels (p=0.004), and systolic blood pressure (p<0.001) than the control participants. Diabetic participants also had increased CVD risk compared to the control group, as assessed using FRS (P<0.001). Participants with DM also had significantly higher cSBP (p=0.003), mean arterial pressure (p<0.001), peripheral PP (p=0.04), FWP (p=0.045) and PWV (p=0.04). The relative expression of miR-146a-5p was significantly increased in the DM group compared to the control group (p=0.02). Across the study cohort, miR-146a-5p expression was significantly associated with waist-to- hip ratio (partial r=0.29, p = 0.002), triglyceride concentrations (partial r=0.2, p = 0.04), the atherogenic index (partial r=0.20, p=0.04) and TNFα concentrations (partial r=0.23, p=0.02), in age, sex and race adjusted analysis. In multivariate adjusted analysis, miR- 146a-5p expression was not associated with any of the arterial function variables (all p>0.05). However, when stratifying participants based on CVD risk, in those with a high risk for CVD (FRS≥20), miR-146a-5p was inversely associated with peripheral PP (Std β=-0.76, p=0.03, cPP (Std β=-0.76, p=0.01), cSBP (Std β=-0.38, p=0.02), FWP (Std β=-0.68, p=0.04) and RWP (Std β=-0.66, p=0.04). When MMP1 was included as a confounder, these associations were no longer significant. Conclusion. MiR-146a-5p expression was significantly higher in participants with T2DM compared to control participants and was significantly associated with traditional CVD risk factors and inflammation. MiR-146a-5p expression was not association with arterial function measures in the total population. Interestingly, in patients at a high risk for CVD, decreased expression of miR-146a-5p was associated with increased pressure pulsatility and wave reflection. These associations were lost when MMP1, a marker of arterial remodelling, was included as a confounding factor. These results suggest that miR-146a-5p may have a regulatory role in the development of arterial dysfunction through arterial remodelling in persons at high risk for CVD. | |
| dc.description.submitter | MM2024 | |
| dc.faculty | Faculty of Health Sciences | |
| dc.identifier | https://orcid.org/ 0000-0002-0085-3383 | |
| dc.identifier.citation | Goldfein, Batsheva. (2024). MicroRNA expression and arterial function in type II diabetes mellitus [Master’s dissertation, University of the Witwatersrand, Johannesburg]. WireDSpace.https://hdl.handle.net/10539/42935 | |
| dc.identifier.uri | https://hdl.handle.net/10539/42935 | |
| dc.language.iso | en | |
| dc.publisher | University of the Witwatersrand, Johannesburg | |
| dc.rights | © 2024 University of the Witwatersrand, Johannesburg. All rights reserved. The copyright in this work vests in the University of the Witwatersrand, Johannesburg. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of University of the Witwatersrand, Johannesburg. | |
| dc.rights.holder | University of the Witwatersrand, Johannesburg | |
| dc.school | School of Physiology | |
| dc.subject | miR-146a-5p | |
| dc.subject | Arterial function | |
| dc.subject | Diabetes | |
| dc.subject | Cardiovascular disease | |
| dc.subject | UCTD | |
| dc.subject.other | SDG-3: Good health and well-being | |
| dc.title | MicroRNA expression and arterial function in type II diabetes mellitus | |
| dc.type | Dissertation |