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

EU-PNAFLD Investigators, Christian A Hudert, Leon A Adams, Anna Alisi, Quentin M Anstee, Annalisa Crudele, Laura G Draijer, Samuel Furse, Jan G Hengstler, Benjamin Jenkins, Kylie Karnebeek, Deirdre A Kelly, Bart G Koot, Albert Koulman, David Meierhofer, Phillip E Melton, Trevor A Mori, Stuart G Snowden, Indra van Mourik, Anita VreugdenhilSusanna Wiegand, Jake P Mann

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1934-1948
Number of pages15
JournalHepatology Communications
Volume6
Issue number8
Early online date11 Apr 2022
DOIs
Publication statusPublished - Aug 2022

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