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Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence

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Melton, PE and Burton, MA and Lillycrop, KA and Godfrey, KM and Rauschert, S and Anderson, D and Burdge, GC and Mori, TA and Beilin, LJ and Ayonrinde, OT and Craig, JM and Olynyk, JK and Holbrook, JD and Pennell, CE and Oddy, WH and Moses, EK and Adams, LA and Huang, RC, Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence, Hepatology International pp. 1-11. ISSN 1936-0533 (2023) [Refereed Article]


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Copyright Statement

The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License, https://creativecommons.org/licenses/by/4.0/ which permits use, sharing, adaptation, distribution and reproduction in any medium or format.

DOI: doi:10.1007/s12072-022-10469-7

Abstract

Background and aims: Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence, we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks.

Approach and results: We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially methylated CpG sites (dmCpGs) for which ≥ 2 probes per gene remained significant across four statistical models with a nominal p value < 0.007. EWAS identified dmCpGs related to three genes (ANK1, MIR10a, PTPRN2) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced (ANK1 n = 6, MIR10a n = 7, PTPRN2 n = 3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p < 2.3 10-3).

Conclusions: We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.

Item Details

Item Type:Refereed Article
Keywords:epigenetics, DNA Methylation, EWAS, ANK1, MIR10Am PTPRN2
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Gastroenterology and hepatology
Objective Division:Health
Objective Group:Specific population health (excl. Indigenous health)
Objective Field:Adolescent health
UTAS Author:Melton, PE (Dr Phillip Melton)
UTAS Author:Oddy, WH (Professor Wendy Oddy)
ID Code:155444
Year Published:2023
Funding Support:National Health and Medical Research Council (2001203)
Deposited By:Menzies Institute for Medical Research
Deposited On:2023-02-20
Last Modified:2023-03-21
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