Dataset Information

Adiposity, metabolomic biomarkers, and risk of nonalcoholic fatty liver disease: a case-cohort study.

ABSTRACT:

Background

Globally, the burden of obesity and associated nonalcoholic fatty liver disease (NAFLD) are rising, but little is known about the role that circulating metabolomic biomarkers play in mediating their association.

Objectives

We aimed to examine the observational and genetic associations of adiposity with metabolomic biomarkers and the observational associations of metabolomic biomarkers with incident NAFLD.

Methods

A case-subcohort study within the prospective China Kadoorie Biobank included 176 NAFLD cases and 180 subcohort individuals and measured 1208 metabolites in stored baseline plasma using a Metabolon assay. In the subcohort the observational and genetic associations of BMI with biomarkers were assessed using linear regression, with adjustment for multiple testing. Cox regression was used to estimate adjusted HRs for NAFLD associated with biomarkers.

Results

In observational analyses, BMI (kg/m2; mean: 23.9 in the subcohort) was associated with 199 metabolites at a 5% false discovery rate. The effects of genetically elevated BMI with specific metabolites were directionally consistent with the observational associations. Overall, 35 metabolites were associated with NAFLD risk, of which 15 were also associated with BMI, including glutamate (HR per 1-SD higher metabolite: 1.95; 95% CI: 1.48, 2.56), cysteine-glutathione disulfide (0.44; 0.31, 0.62), diaclyglycerol (C32:1) (1.71; 1.24, 2.35), behenoyl dihydrosphingomyelin (C40:0) (1.92; 1.42, 2.59), butyrylcarnitine (C4) (1.91; 1.38, 2.35), 2-hydroxybehenate (1.81; 1.34, 2.45), and 4-cholesten-3-one (1.79; 1.27, 2.54). The discriminatory performance of known risk factors was increased when 28 metabolites were also considered simultaneously in the model (weighted C-statistic: 0.84 to 0.90; P < 0.001).

Conclusions

Among relatively lean Chinese adults, a range of metabolomic biomarkers are associated with NAFLD risk and these biomarkers may lie on the pathway between adiposity and NAFLD.

SUBMITTER: Pang Y

PROVIDER: S-EPMC8895224 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNonalcoholic fatty liver disease (NAFLD) is the most common liver disease. Metabolism-related genes significantly influence the onset and progression of the disease. Hence, it is necessary to screen metabolism-related biomarkers for the diagnosis and treatment of NAFLD patients.MethodsGSE48452, GSE63067, and GSE89632 datasets including nonalcoholic steatohepatitis (NASH) and healthy controls (HC) analyzed in this study were retrieved from the Gene Expression Omnibus (GEO) database. First, differentially expressed genes (DEGs) between NASH and HC samples were obtained. Next, metabolism-related DEGs (MR-DEGs) were identified by overlapping DEGs and metabolism-related genes (MRG). Further, a protein-protein interaction (PPI) network was developed to show the interaction among MR-DEGs. Subsequently, the "Least absolute shrinkage and selection operator regression" and "Random Forest" algorithms were used to screen metabolism-related genes (MRGs) in patients with NAFLD. Next, immune cell infiltration and gene set enrichment analyses (GSEA) were performed on these metabolism-related genes. Finally, the expression of metabolism-related gene was determined at the transcription level.ResultsFirst, 129 DEGs related to NAFLD development were identified among patients with nonalcoholic steatohepatitis (NASH) and healthy control. Next, 18 MR-DEGs were identified using the Venn diagram. Subsequently, four genes, including AMDHD1, FMO1, LPL, and P4HA1, were identified using machine learning algorithms. Moreover, a regulatory network consisting of four genes, 25 microRNAs (miRNAs), and 41 transcription factors (TFs) was constructed. Finally, a significant increase in FMO1 and LPL expression levels and a decrease in AMDHD1 and P4HA1 expression levels were observed in patients in the NASH group compared to the HC group.ConclusionMetabolism-related genes associated with NAFLD were identified, containing AMDHD1, FMO1, LPL, and P4HA1, which provide insights into diagnosing and treating patients with NAFLD.