Document Type
Journal Article
Publication Title
Hepatology International
PubMed ID
36737504
Publisher
Springer
School
School of Medical and Health Sciences
RAS ID
56496
Funders
National and Medical Research Council (NHMRC) / Fremantle Hospital Research Foundation / Gastroenterology Society of Australia / Department of Health, Western Australia FutureHealth fund in connection with the European Union's Horizon2020 grant (#733206) / UK Medical Research Council (MC_UU_12011/4) / National Institute for Health Research (NIHR Senior Investigator (NF-SI-0515–10042) / NIHR Southampton Biomedical Research Centre
Grant Number
NHMRC Numbers : 1059711, 353514, 403981, 1053384, 1136046, 1142858
Grant Link
http://purl.org/au-research/grants/nhmrc/1059711 http://purl.org/au-research/grants/nhmrc/353514 http://purl.org/au-research/grants/nhmrc/403981 http://purl.org/au-research/grants/nhmrc/1053384 http://purl.org/au-research/grants/nhmrc/1136046 http://purl.org/au-research/grants/nhmrc/1142858
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.
DOI
10.1007/s12072-022-10469-7
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Melton, P. E., Burton, M. A., Lillycrop, K., Godfrey, K. M., Rauschert, S., Anderson, D., ... & Huang, R. C. (2023). Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence, Hepatology International, 17, 584-594.
https://doi.org/10.1007/s12072-022-10469-7