Variants in MTARC1 and HSD17B13 reduce severity of NAFLD in children and suppress fibrotic pathways through distinct mechanisms
van Mourik, Indra
Wiley Open Access
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Hudert, C., Adams, L., Alisi, A., Anstee, Q., Crudele, A., Draijer, L., Furse, S., et al. Variants in MTARC1 and HSD17B13 reduce severity of NAFLD in children and suppress fibrotic pathways through distinct mechanisms. Hepatology Communications https://doi.org/10.17863/CAM.82921
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.
CAH, DM and SW are supported by the German Systems Biology Program “LiSyM” (grant no. 31L0057 and 31L0058) sponsored by the German Federal Ministry of Education and Research (BMBF). JPM is supported by a Wellcome Trust fellowship (216329/Z/19/Z), a European Society for Paediatric Research (ESPR) Young Investigator Award, and a Children’s Liver Disease Foundation Grant. TAM is supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia (NHMRC) [Grant number 1136046]. EU-PNAFLD Registry is supported by an European Association for Study of the Liver (EASL) Registry Grant and by the Newcastle NIHR Biomedical Research Centre/Newcastle University using a database infrastructure developed by the EU EPoS consortium. AA is supported by grant from Italian Ministry of Health (5x1000). SF was supported by funding form BBSRC (BB/M027252/1, original proposal written by AK). BK is supported by grants from Van den Broek Lohman Foundation, Virtutis Opus Foundation and For Wishdom Foundation. QMA in a Newcastle NIHR Biomedical Research Centre investigator and a member of the EU H2020 EPoS (Elucidating Pathways of Steatohepatitis) and EU IMI2 LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) consortia funded under grant agreements 634413 and 777377 respectively. This Raine Study was supported by the NHMRC [grant numbers 403981, 353514 and 572613].
Wellcome Trust (204017/Z/16/Z)
Children's Liver Disease Foundation (unknown)
European Society for Paediatric Research (ESPR) (Unknown)
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This record's DOI: https://doi.org/10.17863/CAM.82921
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335490
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/