eCite Digital Repository

Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17-beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms

Citation

Hudert, CA and Adams, LA and Alisi, A and Anstee, QM and Crudele, A and Draijer, LG and Furse, S and Hengstler, JG and Jenkins, B and Karnebeek, K and Kelly, DA and Koot, BG and Koulman, A and Meierhofer, D and Melton, PE and Mori, TA and Snowden, GS and van Mourik, I and Vreugdenhil, A and Wiegand, S and Mann, JP, EU-PNAFLD investigators, Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17-beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms, Hepatology communications, 6, (8) pp. 1934-1948. ISSN 2471-254X (2022) [Refereed Article]


Preview
PDF (Fully published version)
6Mb
  

Copyright Statement

2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution License. Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

DOI: doi:10.1002/hep4.1955

Abstract

Genome-wide association studies in adults have identified variants in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) and mitochondrial amidoxime reducing component 1 (MTARC1) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in patatin-like phospholipase domain-containing protein 3 (PNPLA3). Genotype-histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T>TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7; 95% confidence interval, 0.6-0.9) and a lower grade of portal inflammation (p < 0.001). rs2642438G>A in MTARC1 was associated with a lower grade of hepatic steatosis (p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective -TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down-regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1. Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.

Item Details

Item Type:Refereed Article
Keywords:pediatric NAFLD, Fibrosis, Genetics, HSD17B13, MTARC1
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Gene mapping
Objective Division:Health
Objective Group:Public health (excl. specific population health)
Objective Field:Overweight and obesity
UTAS Author:Melton, PE (Dr Phillip Melton)
ID Code:153567
Year Published:2022
Web of Science® Times Cited:3
Deposited By:Menzies Institute for Medical Research
Deposited On:2022-09-26
Last Modified:2022-11-01
Downloads:1 View Download Statistics

Repository Staff Only: item control page