Profiling of cell-free DNA methylation and histone signatures in pediatric NAFLD: A pilot study.

Buzova, D; Braghini, MR; Bianco, SD; Lo Re, O; Raffaele, M; Frohlich, J; Kisheva, A; Crudele, A; Mosca, A; Sartorelli, MR; Balsano, C; Cerveny, J; Mazza, T; Alisi, A; Vinciguerra, M

Profiling of cell-free DNA methylation and histone signatures in pediatric NAFLD: A pilot study.

Buzova, D Braghini, MR Bianco, SD Lo Re, O Raffaele, M Frohlich, J Kisheva, A Crudele, A Mosca, A Sartorelli, MR Balsano, C Cerveny, J

Mazza, T Alisi, A Vinciguerra, M

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Publisher:: JOHN WILEY & SONS LTD
Publication Type:: Journal Article
Citation:: Hepatol Commun, 2022, 6, (12), pp. 3311-3323
Issue Date:: 2022-12

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Field	Value	Language
dc.contributor.author	Buzova, D
dc.contributor.author	Braghini, MR
dc.contributor.author	Bianco, SD
dc.contributor.author	Lo Re, O
dc.contributor.author	Raffaele, M
dc.contributor.author	Frohlich, J
dc.contributor.author	Kisheva, A
dc.contributor.author	Crudele, A
dc.contributor.author	Mosca, A
dc.contributor.author	Sartorelli, MR
dc.contributor.author	Balsano, C
dc.contributor.author	Cerveny, J https://orcid.org/0000-0002-5046-3105
dc.contributor.author	Mazza, T
dc.contributor.author	Alisi, A
dc.contributor.author	Vinciguerra, M
dc.date.accessioned	2023-06-05T04:37:11Z
dc.date.available	2022-08-10
dc.date.available	2023-06-05T04:37:11Z
dc.date.issued	2022-12
dc.identifier.citation	Hepatol Commun, 2022, 6, (12), pp. 3311-3323
dc.identifier.issn	2471-254X
dc.identifier.issn	2471-254X
dc.identifier.uri	http://hdl.handle.net/10453/170638
dc.description.abstract	Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children and adolescents, increasing the risk of its progression toward nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. There is an urgent need for noninvasive early diagnostic and prognostic tools such as epigenetic marks (epimarks), which would replace liver biopsy in the future. We used plasma samples from 67 children with biopsy-proven NAFLD, and as controls we used samples from 20 children negative for steatosis by ultrasound. All patients were genotyped for patatin-like phospholipase domain containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O-acyltransferase domain containing 7 (MBOAT7), and klotho-β (KLB) gene variants, and data on anthropometric and biochemical parameters were collected. Furthermore, plasma cell-free DNA (cfDNA) methylation was quantified using a commercially available kit, and ImageStream(X) was used for the detection of free circulating histone complexes and variants. We found a significant enrichment of the levels of histone macroH2A1.2 in the plasma of children with NAFLD compared to controls, and a strong correlation between cfDNA methylation levels and NASH. Receiver operating characteristic curve analysis demonstrated that combination of cfDNA methylation, PNPLA3 rs738409 variant, coupled with either high-density lipoprotein cholesterol or alanine aminotransferase levels can strongly predict the progression of pediatric NAFLD to NASH with area under the curve >0.87. Conclusion: Our pilot study combined epimarks and genetic and metabolic markers for a robust risk assessment of NAFLD development and progression in children, offering a promising noninvasive tool for the consistent diagnosis and prognosis of pediatric NAFLD. Further studies are necessary to identify their pathogenic origin and function.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	JOHN WILEY & SONS LTD
dc.relation.ispartof	Hepatol Commun
dc.relation.isbasedon	10.1002/hep4.2082
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Adolescent
dc.subject.mesh	Humans
dc.subject.mesh	Child
dc.subject.mesh	Non-alcoholic Fatty Liver Disease
dc.subject.mesh	Histones
dc.subject.mesh	Pilot Projects
dc.subject.mesh	Lipase
dc.subject.mesh	Cell-Free Nucleic Acids
dc.subject.mesh	DNA Methylation
dc.subject.mesh	Membrane Proteins
dc.subject.mesh	Humans
dc.subject.mesh	Lipase
dc.subject.mesh	Membrane Proteins
dc.subject.mesh	Histones
dc.subject.mesh	Pilot Projects
dc.subject.mesh	DNA Methylation
dc.subject.mesh	Adolescent
dc.subject.mesh	Child
dc.subject.mesh	Non-alcoholic Fatty Liver Disease
dc.subject.mesh	Cell-Free Nucleic Acids
dc.subject.mesh	Adolescent
dc.subject.mesh	Humans
dc.subject.mesh	Child
dc.subject.mesh	Non-alcoholic Fatty Liver Disease
dc.subject.mesh	Histones
dc.subject.mesh	Pilot Projects
dc.subject.mesh	Lipase
dc.subject.mesh	Cell-Free Nucleic Acids
dc.subject.mesh	DNA Methylation
dc.subject.mesh	Membrane Proteins
dc.title	Profiling of cell-free DNA methylation and histone signatures in pediatric NAFLD: A pilot study.
dc.type	Journal Article
utslib.citation.volume	6
utslib.location.activity	United States
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
utslib.copyright.status	open_access	*
dc.date.updated	2023-06-05T04:37:06Z
pubs.issue	12
pubs.publication-status	Published
pubs.volume	6
utslib.citation.issue	12

Abstract:

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children and adolescents, increasing the risk of its progression toward nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. There is an urgent need for noninvasive early diagnostic and prognostic tools such as epigenetic marks (epimarks), which would replace liver biopsy in the future. We used plasma samples from 67 children with biopsy-proven NAFLD, and as controls we used samples from 20 children negative for steatosis by ultrasound. All patients were genotyped for patatin-like phospholipase domain containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O-acyltransferase domain containing 7 (MBOAT7), and klotho-β (KLB) gene variants, and data on anthropometric and biochemical parameters were collected. Furthermore, plasma cell-free DNA (cfDNA) methylation was quantified using a commercially available kit, and ImageStream(X) was used for the detection of free circulating histone complexes and variants. We found a significant enrichment of the levels of histone macroH2A1.2 in the plasma of children with NAFLD compared to controls, and a strong correlation between cfDNA methylation levels and NASH. Receiver operating characteristic curve analysis demonstrated that combination of cfDNA methylation, PNPLA3 rs738409 variant, coupled with either high-density lipoprotein cholesterol or alanine aminotransferase levels can strongly predict the progression of pediatric NAFLD to NASH with area under the curve >0.87. Conclusion: Our pilot study combined epimarks and genetic and metabolic markers for a robust risk assessment of NAFLD development and progression in children, offering a promising noninvasive tool for the consistent diagnosis and prognosis of pediatric NAFLD. Further studies are necessary to identify their pathogenic origin and function.

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http://hdl.handle.net/10453/170638