Abstract
Original language | English |
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Pages (from-to) | 1934-1948 |
Number of pages | 15 |
Journal | Hepatology communications |
Volume | 6 |
Issue number | 8 |
DOIs | |
Publication status | Published - 1 Aug 2022 |
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In: Hepatology communications, Vol. 6, No. 8, 01.08.2022, p. 1934-1948.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - 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
AU - Hudert, Christian A.
AU - Adams, Leon A.
AU - Alisi, Anna
AU - Anstee, Quentin M.
AU - Crudele, Annalisa
AU - Draijer, Laura G.
AU - Furse, Samuel
AU - Hengstler, Jan G.
AU - Jenkins, Benjamin
AU - Karnebeek, Kylie
AU - Kelly, Deirdre A.
AU - Koot, Bart G.
AU - Koulman, Albert
AU - Meierhofer, David
AU - Melton, Phillip E.
AU - Mori, Trevor A.
AU - Snowden, Stuart G.
AU - van Mourik, Indra
AU - Vreugdenhil, Anita
AU - Wiegand, Susanna
AU - EU-PNAFLD investigators
AU - Mann, Jake P.
N1 - Funding Information: German Federal Ministry of Education and Research, German Systems Biology Program “LiSyM,” Grant Numbers: 31L0057, 31L0058. Wellcome Trust, Fellowship Number: 216329/Z/19/Z. European Society for Paediatric Research Young Investigator Award. Children’s Liver Disease Foundation Grant. National Health and Medical Research Council of Australia, Senior Research Fellowship Number: 1136046. European Association for Study of the Liver, Registry Grant. Newcastle National Institute for Health Research (NIHR) Biomedical Research Centre/Newcastle University. Italian Ministry of Health (51000). Biotechnology and Biological Sciences Research Council, Grant Number: BB/M027252/1. Van den Broek Lohman Foundation. Virtutis Opus Foundation. For Wishdom Foundation. Newcastle NIHR Biomedical Research Centre. European Union (EU) H2020 Elucidating Pathways of Steatohepatitis Consortium, Grant Agreement: 634413. EU IMI2 Liver Investigation: Testing Marker Utility in Steatohepatitis Consortium, Grant Agreement: 777377. National Health and Medical Research Council, Grant Numbers: 403981, 353514, 572613. No study sponsors had any role in the study design or data collection, analysis, and interpretation × Funding Information: German Federal Ministry of Education and Research, German Systems Biology Program “LiSyM,” Grant Numbers: 31L0057, 31L0058. Wellcome Trust, Fellowship Number: 216329/Z/19/Z. European Society for Paediatric Research Young Investigator Award. Children’s Liver Disease Foundation Grant. National Health and Medical Research Council of Australia, Senior Research Fellowship Number: 1136046. European Association for Study of the Liver, Registry Grant. Newcastle National Institute for Health Research (NIHR) Biomedical Research Centre/Newcastle University. Italian Ministry of Health (5 × 1000). Biotechnology and Biological Sciences Research Council, Grant Number: BB/M027252/1. Van den Broek Lohman Foundation. Virtutis Opus Foundation. For Wishdom Foundation. Newcastle NIHR Biomedical Research Centre. European Union (EU) H2020 Elucidating Pathways of Steatohepatitis Consortium, Grant Agreement: 634413. EU IMI2 Liver Investigation: Testing Marker Utility in Steatohepatitis Consortium, Grant Agreement: 777377. National Health and Medical Research Council, Grant Numbers: 403981, 353514, 572613. No study sponsors had any role in the study design or data collection, analysis, and interpretation The authors are grateful to the Raine Study participants and their families, and to the Raine Study research staff for cohort coordination and data collection. The authors gratefully acknowledge the following institutes for providing funding for Core Management of the Raine Study: University of Western Australia (UWA); Curtin University; Raine Medical Research Foundation; UWA Faculty of Medicine, Dentistry, and Health Sciences; Telethon Kids Institute, Women and Infants Research Foundation (King Edward Memorial Hospital); Edith Cowan University; Murdoch University and University of Notre Dame Australia; Gastroenterological Society of Australia; Fremantle Hospital (Perth, Australia). We thank Rita De Vito (Rome) for the expert pathology review of liver biopsies and the late Valerio Nobili for his contribution to this project. Publisher Copyright: © 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85130166692&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/hep4.1955
DO - https://doi.org/10.1002/hep4.1955
M3 - Article
C2 - 35411667
SN - 2471-254X
VL - 6
SP - 1934
EP - 1948
JO - Hepatology communications
JF - Hepatology communications
IS - 8
ER -