Insights into genetic variants associated with NASH-fibrosis from metabolite profiling.

Autor:	Mann JP; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK., Pietzner M; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK., Wittemans LB; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK., Rolfe EL; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK., Kerrison ND; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK., Imamura F; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK., Forouhi NG; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK., Fauman E; Internal Medicine Research Unit, Pfizer Worldwide Research, Development and Medical, Cambridge, MA 02142, USA., Allison ME; Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK., Griffin JL; MRC Human Nutrition Research, University of Cambridge, Cambridge CB1 9NL, UK.; Department of Biochemistry, Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, UK., Koulman A; MRC Human Nutrition Research, University of Cambridge, Cambridge CB1 9NL, UK.; Department of Biochemistry, Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, UK., Wareham NJ; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK., Langenberg C; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2020 Dec 18; Vol. 29 (20), pp. 3451-3463.
DOI:	10.1093/hmg/ddaa162
Abstrakt:	Several genetic discoveries robustly implicate five single-nucleotide variants in the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and fibrosis (NASH-fibrosis), including a recently identified variant in MTARC1. To better understand these variants as potential therapeutic targets, we aimed to characterize their impact on metabolism using comprehensive metabolomics data from two population-based studies. A total of 9135 participants from the Fenland study and 9902 participants from the EPIC-Norfolk cohort were included in the study. We identified individuals with risk alleles associated with NASH-fibrosis: rs738409C>G in PNPLA3, rs58542926C>T in TM6SF2, rs641738C>T near MBOAT7, rs72613567TA>T in HSD17B13 and rs2642438A>G in MTARC1. Circulating levels of 1449 metabolites were measured using targeted and untargeted metabolomics. Associations between NASH-fibrosis variants and metabolites were assessed using linear regression. The specificity of variant-metabolite associations were compared to metabolite associations with ultrasound-defined steatosis, gene variants linked to liver fat (in GCKR, PPP1R3B and LYPLAL1) and gene variants linked to cirrhosis (in HFE and SERPINA1). Each NASH-fibrosis variant demonstrated a specific metabolite profile with little overlap (8/97 metabolites) comprising diverse aspects of lipid metabolism. Risk alleles in PNPLA3 and HSD17B13 were both associated with higher 3-methylglutarylcarnitine and three variants were associated with lower lysophosphatidylcholine C14:0. The risk allele in MTARC1 was associated with higher levels of sphingomyelins. There was no overlap with metabolites that associated with HFE or SERPINA1 variants. Our results suggest a link between the NASH-protective variant in MTARC1 to the metabolism of sphingomyelins and identify distinct molecular patterns associated with each of the NASH-fibrosis variants under investigation. (© The Author(s) 2020. Published by Oxford University Press.)
Databáze:	MEDLINE
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