Circulating MicroRNA-122 is associated with the risk of new-onset metabolic syndrome and type 2 diabetes

Peter Willeit; Philipp Skroblin; Alexander R. Moschen; Xiaoke Yin; Dorothee Kaudewitz; Anna Zampetaki; Temo Barwari; Meredith Whitehead; Cristina M. Ramírez; Leigh Goedeke; Noemi Rotllan; Enzo Bonora; Alun D. Hughes; Peter Santer; Carlos Fernández-Hernando; Herbert Tilg; Johann Willeit; Stefan Kiechl; Manuel Mayr

doi:10.2337/db16-0731

Circulating MicroRNA-122 is associated with the risk of new-onset metabolic syndrome and type 2 diabetes

Peter Willeit^*, Philipp Skroblin, Alexander R. Moschen, Xiaoke Yin, Dorothee Kaudewitz, Anna Zampetaki, Temo Barwari, Meredith Whitehead, Cristina M. Ramírez, Leigh Goedeke, Noemi Rotllan, Enzo Bonora, Alun D. Hughes, Peter Santer, Carlos Fernández-Hernando, Herbert Tilg, Johann Willeit, Stefan Kiechl, Manuel Mayr

^*Corresponding author for this work

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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-a-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.

Original language	English
Pages (from-to)	347-357
Number of pages	11
Journal	Diabetes
Volume	66
Issue number	2
Early online date	29 Nov 2016
DOIs	https://doi.org/10.2337/db16-0731
Publication status	Published - 1 Feb 2017

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Circulating_MicroRNA_122_ZAMPETAKI_Publishedonline29November2016_GREEN_AAMAccepted author manuscript, 295 KB

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Willeit, P., Skroblin, P., Moschen, A. R., Yin, X., Kaudewitz, D., Zampetaki, A., Barwari, T., Whitehead, M., Ramírez, C. M., Goedeke, L., Rotllan, N., Bonora, E., Hughes, A. D., Santer, P., Fernández-Hernando, C., Tilg, H., Willeit, J., Kiechl, S., & Mayr, M. (2017). Circulating MicroRNA-122 is associated with the risk of new-onset metabolic syndrome and type 2 diabetes. Diabetes, 66(2), 347-357. https://doi.org/10.2337/db16-0731

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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-a-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.",

author = "Peter Willeit and Philipp Skroblin and Moschen, {Alexander R.} and Xiaoke Yin and Dorothee Kaudewitz and Anna Zampetaki and Temo Barwari and Meredith Whitehead and Ram{\'i}rez, {Cristina M.} and Leigh Goedeke and Noemi Rotllan and Enzo Bonora and Hughes, {Alun D.} and Peter Santer and Carlos Fern{\'a}ndez-Hernando and Herbert Tilg and Johann Willeit and Stefan Kiechl and Manuel Mayr",

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Willeit, P, Skroblin, P, Moschen, AR, Yin, X, Kaudewitz, D, Zampetaki, A , Barwari, T , Whitehead, M, Ramírez, CM, Goedeke, L, Rotllan, N, Bonora, E, Hughes, AD, Santer, P, Fernández-Hernando, C, Tilg, H, Willeit, J, Kiechl, S & Mayr, M 2017, 'Circulating MicroRNA-122 is associated with the risk of new-onset metabolic syndrome and type 2 diabetes', Diabetes, vol. 66, no. 2, pp. 347-357. https://doi.org/10.2337/db16-0731

TY - JOUR

T1 - Circulating MicroRNA-122 is associated with the risk of new-onset metabolic syndrome and type 2 diabetes

AU - Willeit, Peter

AU - Skroblin, Philipp

AU - Moschen, Alexander R.

AU - Yin, Xiaoke

AU - Kaudewitz, Dorothee

AU - Zampetaki, Anna

AU - Barwari, Temo

AU - Whitehead, Meredith

AU - Ramírez, Cristina M.

AU - Goedeke, Leigh

AU - Rotllan, Noemi

AU - Bonora, Enzo

AU - Hughes, Alun D.

AU - Santer, Peter

AU - Fernández-Hernando, Carlos

AU - Tilg, Herbert

AU - Willeit, Johann

AU - Kiechl, Stefan

AU - Mayr, Manuel

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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-a-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.

AB - 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-a-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.

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UR - http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0731/-/DC1.

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DO - 10.2337/db16-0731

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SN - 0012-1797

VL - 66

SP - 347

EP - 357

JO - Diabetes

JF - Diabetes

IS - 2

ER -

Circulating MicroRNA-122 is associated with the risk of new-onset metabolic syndrome and type 2 diabetes

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