Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence
Year: 2023
Type: article
Study design: Observational Study
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 & 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 x 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.
Source: Hepatology International
Institutions: University of Tasmania, The University of Western Australia, Menzies Institute for Medical Research, University of Southampton, University Hospital Southampton NHS Foundation Trust, NIHR Southampton Biomedical Research Centre, The Kids Research Institute Australia, Fiona Stanley Hospital, Fremantle Hospital, Fiona Stanley Fremantle Hospitals Group, Royal Children's Hospital, Deakin University, Murdoch Children's Research Institute, Edith Cowan University, University of Newcastle Australia
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,590
Funders: University of Notre Dame, Australian Government, National Institute for Health and Care Research, European Commission, Raine Medical Research Foundation, Women and Infants Research Foundation, Curtin University of Technology, Edith Cowan University, Murdoch University, University of Notre Dame Australia, Government of Western Australia, NIHR BioResource, Medical Research Council, National Health and Medical Research Council
Awards: Early Life Programming of Cardiovascular Disease, THE CYCLE OF OBESITY: Two generations of a pregnancy cohort to investigate obesity epigenetics, Early-life stressors and LifeCycle health, Childhood Risk Factors for Adult Heart Disease, Obesity and Diabetes - 16 year follow up of a Longitudinal Study, LIFECYCLE - Early Life Stressors and LifeCycle Health, G4217520315, Determinants of Child Health and development, NIHR Senior Investigator Award, Nutrition, Development and Lifelong Health: Studies in European Populations, Investigating the mechanisms and preventative strategies to alleviate the burden of cardiovascular disease
OpenAlex ID: W4319069281