Circulatory microRNAs as potential biomarkers for fatty liver disease: the Rotterdam study

Xiaofang Zhang; Michelle Mens; Yasir Abozaid; Daniel Bos; Sarwa Darwish Murad; Rob de Knegt; Arfan Ikram; Qiuwei Pan; Mohsen Ghanbari

doi:10.1111/apt.16177

Circulatory microRNAs as potential biomarkers for fatty liver disease: the Rotterdam study

Xiaofang Zhang, Michelle Mens, Yasir Abozaid, Daniel Bos, Sarwa Darwish Murad, Rob de Knegt, Arfan Ikram, Qiuwei Pan, Mohsen Ghanbari

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background: Fatty liver disease (FLD) is the most common cause of liver dysfunction in developed countries. There is great interest in developing clinically valid and minimally invasive biomarkers to enhance early diagnosis of FLD. Aim: To investigate the potential of circulatory microRNAs (miRNAs) as biomarkers of FLD at the population level. Methods: Plasma levels of 2083 miRNAs were measured by RNA sequencing in 1999 participants from the prospective population-based Rotterdam Study cohort. The Hounsfield Unit (HU) attenuation of liver was measured using non-enhanced computed tomography (CT) scan. Logistic and linear regression models adjusting for potential confounders were used to examine the association of circulatory miRNAs with liver enzymes (n = 1991) and CT-based FLD (n = 954). Moreover, the association of miRNAs with hepatic steatosis and liver fibrosis was assessed longitudinally in individuals who underwent abdominal ultrasound (n = 1211) and transient elastography (n = 777) after a median follow-up of >6 years. Results: Cross-sectional analysis showed 61 miRNAs significantly associated with serum gamma-glutamyl transferase and/or alkaline phosphatase levels (Bonferroni-corrected P < 8.46 × 10⁻⁵). Moreover, 17 miRNAs were significantly associated with CT-based FLD (P < 8.46 × 10⁻⁵); 14 were among miRNAs associated with liver enzymes. Longitudinal analysis showed that 4 of these 14 miRNAs (miR-193a-5p, miR-122-5p, miR-378d and miR-187-3p) were significantly associated with hepatic steatosis (P < 3.57 × 10⁻³) and three (miR-193a-5p, miR-122-5p and miR-193b-3p) were nominally associated with liver fibrosis (P < 0.05). Nine of the 14 identified miRNAs were involved in pathways underlying liver diseases. Conclusions: Plasma levels of several miRNAs can be used as biomarkers of FLD, laying the groundwork for future clinical applications.

Original language	English
Pages (from-to)	432-442
Number of pages	11
Journal	Alimentary Pharmacology and Therapeutics
Volume	53
Issue number	3
DOIs	https://doi.org/10.1111/apt.16177
Publication status	Published - Feb 2021

Bibliographical note

Funding Information:
Funding The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. MiRNA expression analyses by HTG EdgeSeq WTA were funded by Johnson & Johnson. All authors are grateful to the Rotterdam Study participants, the staff involved with the Rotterdam Study, and the participating general practitioners and pharmacists. We thank the members of the VERI/O laboratory, and bioinformatics teams of HTG Molecular Diagnostics, Tucson, Arizona for performing the miRNA expression analyses by HTG EdgeSeq WTA. Declaration of personal interests: None.

Funding Information:
The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. MiRNA expression analyses by HTG EdgeSeq WTA were funded by Johnson & Johnson.

Publisher Copyright:
© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd

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Cite this

@article{2409cc110e504e8ca89c7cfeb344e2ed,

title = "Circulatory microRNAs as potential biomarkers for fatty liver disease: the Rotterdam study",

abstract = "Background: Fatty liver disease (FLD) is the most common cause of liver dysfunction in developed countries. There is great interest in developing clinically valid and minimally invasive biomarkers to enhance early diagnosis of FLD. Aim: To investigate the potential of circulatory microRNAs (miRNAs) as biomarkers of FLD at the population level. Methods: Plasma levels of 2083 miRNAs were measured by RNA sequencing in 1999 participants from the prospective population-based Rotterdam Study cohort. The Hounsfield Unit (HU) attenuation of liver was measured using non-enhanced computed tomography (CT) scan. Logistic and linear regression models adjusting for potential confounders were used to examine the association of circulatory miRNAs with liver enzymes (n = 1991) and CT-based FLD (n = 954). Moreover, the association of miRNAs with hepatic steatosis and liver fibrosis was assessed longitudinally in individuals who underwent abdominal ultrasound (n = 1211) and transient elastography (n = 777) after a median follow-up of >6 years. Results: Cross-sectional analysis showed 61 miRNAs significantly associated with serum gamma-glutamyl transferase and/or alkaline phosphatase levels (Bonferroni-corrected P < 8.46 × 10−5). Moreover, 17 miRNAs were significantly associated with CT-based FLD (P < 8.46 × 10−5); 14 were among miRNAs associated with liver enzymes. Longitudinal analysis showed that 4 of these 14 miRNAs (miR-193a-5p, miR-122-5p, miR-378d and miR-187-3p) were significantly associated with hepatic steatosis (P < 3.57 × 10−3) and three (miR-193a-5p, miR-122-5p and miR-193b-3p) were nominally associated with liver fibrosis (P < 0.05). Nine of the 14 identified miRNAs were involved in pathways underlying liver diseases. Conclusions: Plasma levels of several miRNAs can be used as biomarkers of FLD, laying the groundwork for future clinical applications.",

author = "Xiaofang Zhang and Michelle Mens and Yasir Abozaid and Daniel Bos and {Darwish Murad}, Sarwa and {de Knegt}, Rob and Arfan Ikram and Qiuwei Pan and Mohsen Ghanbari",

note = "Funding Information: Funding The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. MiRNA expression analyses by HTG EdgeSeq WTA were funded by Johnson & Johnson. All authors are grateful to the Rotterdam Study participants, the staff involved with the Rotterdam Study, and the participating general practitioners and pharmacists. We thank the members of the VERI/O laboratory, and bioinformatics teams of HTG Molecular Diagnostics, Tucson, Arizona for performing the miRNA expression analyses by HTG EdgeSeq WTA. Declaration of personal interests: None. Funding Information: The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. MiRNA expression analyses by HTG EdgeSeq WTA were funded by Johnson & Johnson. Publisher Copyright: {\textcopyright} 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd",

year = "2021",

month = feb,

doi = "10.1111/apt.16177",

language = "English",

volume = "53",

pages = "432--442",

journal = "Alimentary Pharmacology and Therapeutics",

issn = "0269-2813",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "3",

}

TY - JOUR

T1 - Circulatory microRNAs as potential biomarkers for fatty liver disease: the Rotterdam study

AU - Zhang, Xiaofang

AU - Mens, Michelle

AU - Abozaid, Yasir

AU - Bos, Daniel

AU - Darwish Murad, Sarwa

AU - de Knegt, Rob

AU - Ikram, Arfan

AU - Pan, Qiuwei

AU - Ghanbari, Mohsen

N1 - Funding Information: Funding The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. MiRNA expression analyses by HTG EdgeSeq WTA were funded by Johnson & Johnson. All authors are grateful to the Rotterdam Study participants, the staff involved with the Rotterdam Study, and the participating general practitioners and pharmacists. We thank the members of the VERI/O laboratory, and bioinformatics teams of HTG Molecular Diagnostics, Tucson, Arizona for performing the miRNA expression analyses by HTG EdgeSeq WTA. Declaration of personal interests: None. Funding Information: The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. MiRNA expression analyses by HTG EdgeSeq WTA were funded by Johnson & Johnson. Publisher Copyright: © 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd

PY - 2021/2

Y1 - 2021/2

N2 - Background: Fatty liver disease (FLD) is the most common cause of liver dysfunction in developed countries. There is great interest in developing clinically valid and minimally invasive biomarkers to enhance early diagnosis of FLD. Aim: To investigate the potential of circulatory microRNAs (miRNAs) as biomarkers of FLD at the population level. Methods: Plasma levels of 2083 miRNAs were measured by RNA sequencing in 1999 participants from the prospective population-based Rotterdam Study cohort. The Hounsfield Unit (HU) attenuation of liver was measured using non-enhanced computed tomography (CT) scan. Logistic and linear regression models adjusting for potential confounders were used to examine the association of circulatory miRNAs with liver enzymes (n = 1991) and CT-based FLD (n = 954). Moreover, the association of miRNAs with hepatic steatosis and liver fibrosis was assessed longitudinally in individuals who underwent abdominal ultrasound (n = 1211) and transient elastography (n = 777) after a median follow-up of >6 years. Results: Cross-sectional analysis showed 61 miRNAs significantly associated with serum gamma-glutamyl transferase and/or alkaline phosphatase levels (Bonferroni-corrected P < 8.46 × 10−5). Moreover, 17 miRNAs were significantly associated with CT-based FLD (P < 8.46 × 10−5); 14 were among miRNAs associated with liver enzymes. Longitudinal analysis showed that 4 of these 14 miRNAs (miR-193a-5p, miR-122-5p, miR-378d and miR-187-3p) were significantly associated with hepatic steatosis (P < 3.57 × 10−3) and three (miR-193a-5p, miR-122-5p and miR-193b-3p) were nominally associated with liver fibrosis (P < 0.05). Nine of the 14 identified miRNAs were involved in pathways underlying liver diseases. Conclusions: Plasma levels of several miRNAs can be used as biomarkers of FLD, laying the groundwork for future clinical applications.

AB - Background: Fatty liver disease (FLD) is the most common cause of liver dysfunction in developed countries. There is great interest in developing clinically valid and minimally invasive biomarkers to enhance early diagnosis of FLD. Aim: To investigate the potential of circulatory microRNAs (miRNAs) as biomarkers of FLD at the population level. Methods: Plasma levels of 2083 miRNAs were measured by RNA sequencing in 1999 participants from the prospective population-based Rotterdam Study cohort. The Hounsfield Unit (HU) attenuation of liver was measured using non-enhanced computed tomography (CT) scan. Logistic and linear regression models adjusting for potential confounders were used to examine the association of circulatory miRNAs with liver enzymes (n = 1991) and CT-based FLD (n = 954). Moreover, the association of miRNAs with hepatic steatosis and liver fibrosis was assessed longitudinally in individuals who underwent abdominal ultrasound (n = 1211) and transient elastography (n = 777) after a median follow-up of >6 years. Results: Cross-sectional analysis showed 61 miRNAs significantly associated with serum gamma-glutamyl transferase and/or alkaline phosphatase levels (Bonferroni-corrected P < 8.46 × 10−5). Moreover, 17 miRNAs were significantly associated with CT-based FLD (P < 8.46 × 10−5); 14 were among miRNAs associated with liver enzymes. Longitudinal analysis showed that 4 of these 14 miRNAs (miR-193a-5p, miR-122-5p, miR-378d and miR-187-3p) were significantly associated with hepatic steatosis (P < 3.57 × 10−3) and three (miR-193a-5p, miR-122-5p and miR-193b-3p) were nominally associated with liver fibrosis (P < 0.05). Nine of the 14 identified miRNAs were involved in pathways underlying liver diseases. Conclusions: Plasma levels of several miRNAs can be used as biomarkers of FLD, laying the groundwork for future clinical applications.

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U2 - 10.1111/apt.16177

DO - 10.1111/apt.16177

M3 - Article

C2 - 33244812

SN - 0269-2813

VL - 53

SP - 432

EP - 442

JO - Alimentary Pharmacology and Therapeutics

JF - Alimentary Pharmacology and Therapeutics

IS - 3

ER -

Circulatory microRNAs as potential biomarkers for fatty liver disease: the Rotterdam study

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