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.
Accepted version
Peer-reviewed
Repository URI
Repository DOI
Type
Change log
Authors
Abstract
Objective Genome-wide association studies in adults have identified variants in HSD17B13 and MTARC1 as protective against NAFLD. We aimed to test their association with paediatric NAFLD, liver histology, and investigate their function using metabolomics. Design One thousand four hundred and fifty children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in PNPLA3. Genotype-histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. Results rs72613567T>TA in HSD17B13 was associated with lower odds of NAFLD diagnosis (OR 0.7 (95%CI 0.6-0.9) and lower grade of portal inflammation (P<0.001). rs2642438G>A in MTARC1 was associated with 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 downregulation 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.
Description
Keywords
Journal Title
Conference Name
Journal ISSN
2471-254X
Volume Title
Publisher
Publisher DOI
Rights
Sponsorship
Children's Liver Disease Foundation (unknown)
European Society for Paediatric Research (ESPR) (Unknown)