Metabolomic insights into associations between adiposity markers and liver cancer risk: Results from a prospective cohort study and Mendelian randomization analysis.

The nested case-control study identified 27 intermediate metabolites associated with both adiposity markers and liver cancer risk, forming an interconnected functional network.

• Study included 322 incident liver cancer cases and 322 cancer-free controls matched 1:1 within the Shanghai Men's Health Study (SMHS)
• SMHS was initiated in 2002-2006, including 61,469 Chinese men aged 40-74 years, followed for over 20 years
• Seven anthropometric measurements were assessed: BMI, waist circumference, waist-to-hip ratio, waist-to-height ratio, a body shape index, hip circumference, and adult weight gain
• Targeted metabolomic profiling was performed on baseline plasma samples covering 186 circulating metabolites
• Participants diagnosed with liver cancer had higher proportions of seropositive hepatitis B surface antigen (63.7%) compared to their matched controls (6.2%)

Pyroglutamic acid demonstrated the most robust consistency, being significantly associated with all seven anthropometric measurements and liver cancer risk.

• Association with BMI: β per doubling = 0.17; 95% CI: [0.09, 0.24]
• Association with liver cancer: odds ratio per doubling = 1.56; 95% CI: [1.13, 2.15]
• Pyroglutamic acid was significantly associated with all seven anthropometric measurements assessed
• This metabolite was identified as the most consistently associated intermediate metabolite across adiposity markers

Pathway analysis highlighted significant alterations in energy, lipid, and amino acid metabolism, with phenylalanine, tyrosine, and tryptophan biosynthesis showing the highest impact.

• Pathway analysis and network analysis were conducted to explore the biological functions of the 27 intermediate metabolites
• Phenylalanine, tyrosine, and tryptophan biosynthesis showed the highest impact among identified pathways
• Results suggest a key role for aromatic amino acid metabolism in adiposity-driven hepatocarcinogenesis
• Significant alterations were identified in energy, lipid, and amino acid metabolism pathways

Parallel mediation analysis demonstrated significant indirect effects via intermediate metabolites for six of the seven anthropometric measurements in relation to liver cancer risk.

• The proportion mediated by the identified metabolite clusters reached 0.16 (95% CI: [0.05, 0.29]) for BMI
• Significant indirect effects were observed for six of the seven anthropometric measurements
• Parallel mediation analysis was employed to quantify the mediating effects through metabolites
• Results suggest a broad metabolic mediation of the adiposity marker-liver cancer association in observational analysis

Mendelian randomization analysis provided evidence supporting potential causality for 23 of 108 initially observed associations between adiposity markers and metabolites.

• Two-sample Mendelian randomization (MR) analysis was performed to investigate potential causal relationships
• 23 of 108 initially observed associations were supported by MR evidence of potential causality
• The strongest association was observed between waist circumference and oxoglutaric acid (βIVW per standard deviation = 0.31; 95% CI: [0.17, 0.43])
• MR findings pinpointed a more specific and limited set of causal metabolic mediators compared to the broader mediation suggested by observational analysis
• A population mismatch existed between the observational (Chinese men) and MR (European ancestry) analyses, which may limit generalizability