期刊
HEPATOLOGY COMMUNICATIONS
卷 6, 期 8, 页码 1934-1948出版社
JOHN WILEY & SONS LTD
DOI: 10.1002/hep4.1955
关键词
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资金
- 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
- University of Notre Dame Australia
- Gastroenterological Society of Australia
- Fremantle Hospital (Perth, Australia)
- University of Western Australia (UWA)
Genome-wide association studies have identified variants in HSD17B13 and MTARC1 genes that are associated with less severe pediatric NAFLD. Metabolomics studies showed that these variants were associated with reduced liver inflammation and steatosis. These findings provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.
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.
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