title: Circulating MicroRNA-122 Is Associated With the Risk of New-Onset Metabolic Syndrome and Type 2 Diabetes.
abstract: MicroRNA-122 (miR-122) is abundant in the liver and involved in lipid homeostasis, but its relevance to the long-term risk of developing metabolic disorders is unknown. We therefore measured circulating miR-122 in the prospective population-based Bruneck Study (n = 810; survey year 1995). Circulating miR-122 was associated with prevalent 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-α-2-glycoprotein and positively with afamin, complement factor H, VLDL-associated apolipoproteins, and lipid subspecies containing monounsaturated and saturated fatty acids. Proteomics analysis of livers from antagomiR-122-treated mice revealed novel regulators of hepatic lipid metabolism that are responsive to miR-122 inhibition. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT, n = 155), 12-month atorvastatin reduced circulating miR-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, multivariable adjusted risk ratios per one-SD higher log miR-122 were 1.60 (95% CI 1.30-1.96; P < 0.001) for metabolic syndrome and 1.37 (1.03-1.82; P = 0.021) for type 2 diabetes. In conclusion, circulating miR-122 is strongly associated with the risk of developing metabolic syndrome and type 2 diabetes in the general population.
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, U.K. peter.willeit@i-med.ac.at manuel.mayr@kcl.ac.uk.|Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.|Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K.
authors.forename: Peter
authors.identifier: 0000-0002-1866-7159
authors.initials: P
authors.lastname: Willeit
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, U.K.
authors.forename: Philipp
authors.initials: P
authors.lastname: Skroblin
authors.affiliation: Department of Internal Medicine I (Endocrinology, Gastroenterology and Metabolic Diseases), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Moschen
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, U.K.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yin
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, U.K.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Kaudewitz
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, U.K.
authors.forename: Anna
authors.initials: A
authors.lastname: Zampetaki
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, U.K.
authors.forename: Temo
authors.initials: T
authors.lastname: Barwari
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, U.K.
authors.forename: Meredith
authors.initials: M
authors.lastname: Whitehead
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Ramírez
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT.
authors.forename: Leigh
authors.initials: L
authors.lastname: Goedeke
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT.
authors.forename: Noemi
authors.initials: N
authors.lastname: Rotllan
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolic Diseases, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Bonora
authors.affiliation: Institute of Cardiovascular Sciences, University College London, London, U.K.
authors.forename: Alun D
authors.initials: AD
authors.lastname: Hughes
authors.affiliation: Department of Laboratory Medicine, Bruneck Hospital, Bruneck, Italy.
authors.forename: Peter
authors.initials: P
authors.lastname: Santer
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
authors.affiliation: Department of Internal Medicine I (Endocrinology, Gastroenterology and Metabolic Diseases), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Herbert
authors.initials: H
authors.lastname: Tilg
authors.affiliation: Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Johann
authors.initials: J
authors.lastname: Willeit
authors.affiliation: Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kiechl
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, U.K. peter.willeit@i-med.ac.at manuel.mayr@kcl.ac.uk.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000070416:Antagomirs; D000069059:Atorvastatin / Q000494:pharmacology / Q000627:therapeutic use; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000378:metabolism*; D050171:Dyslipidemias / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015994:Incidence; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D024821:Metabolic Syndrome / Q000453:epidemiology / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D009765:Obesity / Q000453:epidemiology / Q000378:metabolism*; D009841:Oligonucleotides / Q000494:pharmacology; D015995:Prevalence; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012709:Serum Albumin / Q000378:metabolism; D000075462:Serum Albumin, Human
chemical_list: C088246:AFM protein, human; D000070416:Antagomirs; D002352:Carrier Proteins; D006023:Glycoproteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008079:Lipoproteins, VLDL; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D009841:Oligonucleotides; D012709:Serum Albumin; C520440:antagomir-122; D017242:Complement Factor H; D000069059:Atorvastatin; D000075462:Serum Albumin, Human