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

Authors

Phillip E. Melton
M. A. Burton
K. A. Lillycrop
K. M. Godfrey
S. Rauschert
D. Anderson
G. C. Burdge
T. A. Mori
L. J. Beilin
O. T. Ayonrinde
J. M. Craig
John K. Olynyk, Edith Cowan UniversityFollow
J. D. Holbrook
C. E. Pennell
W. H. Oddy
E. K. Moses
L. A. Adams
R. C. Huang

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

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

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.