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.
Authors
Hudert, Christian A
Alisi, Anna
Crudele, Annalisa
Draijer, Laura G
EU-PNAFLD investigators
Hengstler, Jan G
Jenkins, Benjamin
Karnebeek, Kylie
Kelly, Deirdre A
Koot, Bart G
Meierhofer, David
Melton, Phillip E
Mori, Trevor A
Snowden, Stuart G
van Mourik, Indra
Vreugdenhil, Anita
Wiegand, Susanna
Publication Date
2022-08Journal Title
Hepatol Commun
ISSN
2471-254X
Publisher
Ovid Technologies (Wolters Kluwer Health)
Language
en
Type
Article
This Version
AO
VoR
Metadata
Show full item recordCitation
Hudert, C. A., Adams, L. A., Alisi, A., Anstee, Q. M., Crudele, A., Draijer, L. G., EU-PNAFLD investigators, et al. (2022). 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.. Hepatol Commun https://doi.org/10.1002/hep4.1955
Description
Funder: Children’s Liver Disease Foundation; Id: http://dx.doi.org/10.13039/501100000290
Funder: European Society for Paediatric Research; Id: http://dx.doi.org/10.13039/501100008873
Funder: Virtutis Opus Foundation
Funder: European Association for the Study of the Liver; Id: http://dx.doi.org/10.13039/501100009253
Funder: For Wishdom Foundation
Funder: Italian Ministry of Health
Funder: Van den Broek Lohman Foundation
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.
Keywords
ORIGINAL ARTICLE, ORIGINAL ARTICLES
Sponsorship
European Commission Horizon 2020 (H2020) Societal Challenges (634413)
Biotechnology and Biological Sciences Research Council (BB/M027252/1)
Identifiers
hep41955
External DOI: https://doi.org/10.1002/hep4.1955
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336017
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.