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

Accepted version
Peer-reviewed

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Article

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Authors

Mann, Jake P 
Wittemans, Laura B 
Rolfe, Emmanuela De Lucia 
Kerrison, Nicola D 

Abstract

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.

Description

Keywords

Adult, Aged, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Liver Cirrhosis, Male, Metabolome, Middle Aged, Non-alcoholic Fatty Liver Disease, Polymorphism, Single Nucleotide, Prognosis, Prospective Studies

Journal Title

Hum Mol Genet

Conference Name

Journal ISSN

0964-6906
1460-2083

Volume Title

29

Publisher

Oxford University Press (OUP)

Rights

All rights reserved
Sponsorship
Wellcome Trust (204017/Z/16/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Medical Research Council (MC_UU_12015/1)
MRC (MC_PC_13046)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
MRC (MC_UU_00006/1)
Medical Research Council (MC_UU_12015/5)
MRC (MC_UU_00006/3)
Medical Research Council (MR/P011705/1)
MRC (MC_UU_00014/5)
Medical Research Council (MC_PC_13030)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Medical Research Council (MC_PC_13046)
This work was supported by the Medical Research Council (Lipid Profiling and Signalling, MC UP A90 1006 & Lipid Dynamics and Regulation, MC PC 13030) and grants to MRC Epidemiology Units (MC UU12015/1, MC UU 12015/5, MC_PC_13046, and MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013). JPM is supported by a Wellcome Trust fellowship (216329/Z/19/Z) and a European Society for Paediatric Research Young Investigator Award. MP is supported by a fellowship from the German Research Foundation (DFG PI 1446/2-1).