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

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.

Letter to the editor: The clinically relevant MTARC1 p.Ala165Thr variant impacts neither the fold nor active site architecture of the human mARC1 protein

“…In the article, a comprehensive study on the influence of a common variant of the mitochondrial amidoxime reducing component 1 (gene: MTARC1; protein: mARC1) on nonalcoholic fatty liver disease (NAFLD) in children is presented. [ 1 ]…”

Association of MARC1, ADCY5, and BCO1 Variants with the Lipid Profile, Suggests an Additive Effect for Hypertriglyceridemia in Mexican Adult Men

“…Although the precise role and physiological function of MARC1 are unknown, it has been proposed that this lipid phenotype may hint at a possible physiological mechanism by which MARC1 could participate in NAFLD [ 12 , 30 ]. Accumulating evidence has associated the occurrence of hypertriglyceridemia as a central factor in the progression of the liver, metabolic, and cardiovascular disease [ 27 , 31 ].…”

“…Recently, the rs2642438-A allele has been associated with higher triglyceride levels, lower HDL-c, and low liver enzyme levels [ 9 , 11 ]. It has been shown that MARC1 deficiency can protect against cirrhosis [ 11 ] and decrease the severity of nonalcoholic fatty liver disease (NAFLD); however, the mechanism involved is unclear [ 9 , 12 , 13 ].…”

Reply

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To the editor, We read with great interest the manuscript from Struwe et al [1] and their insightful comment on our recent article. [2] Their X-ray crystallography studies on mARC1 (encoded by MTARC1) illustrate two important general points: the limitation of in silico modeling and the challenge of understanding human variants.In silico modeling of protein structure (and protein variants) is based on assumptions of amino acid interactions and how they combine in higher-level protein folding. Despite enormous progress being made in the field, [3] there is no replacement for the gold standard of X-ray crystallography, as used by Struwe et al For this reason, structural biology will continue to be indispensable for understanding mechanisms and drug discovery.Together, these data suggest that it will be challenging to elucidate the mechanism through which this variant protects against liver disease.

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“…To the editor, We read with great interest the manuscript from Struwe et al [1] and their insightful comment on our recent article. [2] Their X-ray crystallography studies on mARC1 (encoded by MTARC1) illustrate two important general points: the limitation of in silico modeling and the challenge of understanding human variants.…”