Role of Micro-RNA-122 in Cardiometabolic Diseases

Recent discoveries have revealed that microRNAs, small non-coding RNAs, play a key role in the regulation of gene expression. MicroRNA-122 (miR-122) is highly abundant in the liver and has been proposed to play a central role in lipid and glucose homeostasis. Animal studies and small epidemiological studies have shown that miR-122 concentrations in the blood are positively correlated with major lipid classes, such as total cholesterol, and are affected by liver disease, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and viral hepatitis. However, the relevance of miR-122 to cardiometabolic diseases has not yet been investigated in a large-scale epidemiological study. The proposed project will address this uncertainty using the prospective Bruneck Study, a well-established cohort study representative of the general population aged 45-84 years. Major strengths of this unique study include a rigorous phenotypic characterisation of study participants (with information on microRNAs and lipidomics), repeated measurements in 5- year intervals, excellent participation rates, and detailed information on incident cardiometabolic outcomes over a follow-up length of 15 years. The scientific aims of the proposed projects are to: (i) reliably assess cross-sectional associations of miR-122 in plasma and serum with conventional risk markers, liver markers, and lipidomic markers; (ii) quantify the cross-sectional association of miR-122 with the prevalence of cardiometabolic diseases, including metabolic syndrome, type 2 diabetes, and cardiovascular disease; (iii) determine the prospective association of miR-122 with the incidence of cardiometabolic diseases; (iv) explore differences in these associations by sex, body mass index, or intake of medication; and (v) supplement epidemiological findings with experimental studies to provide mechanistic insight. The project is crucial for my personal development, because it would allow me to specialise in postgenomic biomarkers, learn from internationally renowned scientists in the field, and apply novel cutting-edge techniques to Austrian epidemiological studies, when returning to Innsbruck. The host institution is the British Heart Foundation Centre of Research Excellence at Kings College London. Professor Mayrs group spearheads efforts for the translational application of emerging technologies, such as microRNAs, lipidomics, and proteomics to cardiovascular research (www.vascular-proteomics.com). My application builds on an existing long-term successful collaboration between research groups at Innsbruck Medical University and Kings College London, as evidenced by multiple top-ranking and highly cited publications.

Rationale: MicroRNA-122, a small non-coding RNA highly abundant in the liver, plays a key role in the regulation of lipid and glucose metabolism. In humans, the available evidence had been limited to cross-sectional or case-control studies. In the funded project we therefore aimed to quantify long-term associations of circulating microRNA-122 with the development of cardiometabolic diseases and to provide mechanistic insight by conducting a series of experimental studies. Methods and Results: We measured circulating microRNA-122 concentration in serum and plasma samples of the prospective population-based Bruneck Study (n=810; survey year: 1995). In cross-sectional analyses, microRNA-122 was associated with insulin resistance, obesity, metabolic syndrome, type-2 diabetes, and an adverse lipid profile. Among 92 plasma proteins and 135 lipid subspecies quantified with mass spectrometry, it correlated inversely with zinc-alpha-2-glycoprotein and positively with afamin, complement-factor H, apolipoproteins associated with the very-low-density lipoprotein, and lipid subspecies containing monounsaturated and saturated fatty acids. Proteomics analysis of livers from mice, in which microRNA-122 had been inhibited with antagomiR-122 treatment, revealed novel regulators of liver lipid metabolism linked to microRNA-122. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT, n=155), 12-month atorvastatin reduced circulating microRNA-122. A similar response to atorvastatin was observed in mice and cultured murine hepatocytes. Over up to 15 years of follow-up in the Bruneck Study, we observed significant associations of microRNA-122 concentration with the risk of developing metabolic syndrome and type-2 diabetes. Conclusion: Circulating microRNA-122 is strongly associated with the risk of developing metabolic syndrome and type-2 diabetes in the general population. Institutions collaborating in this project: Kings College London, London, UK; Medical University of Innsbruck, Innsbruck, Austria; Yale University School of Medicine, New Haven, CT, USA; University and Hospital Trust of Verona, Verona, Italy; University of Cambridge, Cambridge, UK; University College London, London, UK; and Bruneck Hospital, Bruneck, Italy.