MicroRNAs in Cardiometabolic Disease. With a Focus on miR-483-5p

Beskrivning

Background
Cardiometabolic disease (CMD), comprising type 2 diabetes (T2DM) and cardiovascular disease (CVD) is a worldwide health concern whose pathophysiology starts many years before clinical manifestation. We
hypothesized that alterations of microRNA levels can be traced in the circulation in healthy but CMD prone individuals.

Aims
Using two independent prospective cohort studies, our primary aim was to find consistent associations between serum levels of microRNAs and future risk of T2DM and CVD, as well as with presence of atherosclerosis. The secondary aim was to investigate whether such CMD-related microRNAs were correlated with life-style factors, in order to build hypotheses of how to alter their levels. Finally, by utilizing plasma metabolomics measurements, we test whether CMD-related microRNAs are correlated with alterations in certain metabolic pathways.

Methods
A cDNA synthesis and qPCR-based method was used to determine expressed microRNAs in serum from participants from the Malmö Diet and Cancer-Cardiovascular Cohort (MDC-CC) (N=553), and Malmö Offspring Study (MOS) (N=1223).

Results
Serum levels of circulating miR-483-5p were significantly associated with incident CMD and CMD-related risk factors in both paper-I and paper-II. Moreover, miR-483 5p was associated with carotid intima media thickness (IMT) in MDC-CC and associated with the number of carotid plaques in MOS. However, several
other previously CMD-implicated microRNAs were not reproducibly associated with CMD neither in MDCCC nor in MOS. In Paper-III, mir-483-5p was negatively related to physical activity. Positive correlations were found between miR-483 5p and the plasma levels of the branched-chain amino acids leucine and isoleucine and their catabolites propionylcarnitine and isovalerylcarnitine.

Conclusion
In this thesis, we find novel associations between miR-483-5p and future risk of cardiometabolic disease and its risk factors in two independent prospective cohorts. This highlights two potential future prospects for miR-483 5p. Either miR-483 5p could be used in a biomarker panel to improve risk stratification of
T2DM or CVD or if the associations are causal, being targeted by pharmacological therapies aiming to lower the expression of miR-483 5p.

Period	2018 jan. 1 → 2021 juni 11
Examinerad/handledd person	Widet Gallo
Examination/handledning vid	Kardiovaskulär forskning - hypertoni
Omfattning	Internationell