Insights into genetic variants associated with NASH-fibrosis from metabolite profiling.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
18 12 2020
18 12 2020
Historique:
received:
19
03
2020
revised:
15
06
2020
accepted:
16
07
2020
pubmed:
29
7
2020
medline:
31
8
2021
entrez:
29
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32720691
pii: 5876259
doi: 10.1093/hmg/ddaa162
pmc: PMC7116726
mid: EMS98650
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3451-3463Subventions
Organisme : Medical Research Council
ID : MC_UU_00006/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 216329/Z/19/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12015/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P011705/2
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12015/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00006/3
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_A090_1006
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P011705/1
Pays : United Kingdom
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press.
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