Metabolites and Charcot Foot: A Comprehensive Analysis Through Mendelian Randomization

Area of Science:

• Metabolomics
• Genetics
• Diabetology

Background:

• Charcot foot is a complex condition potentially influenced by metabolites.
• Previous research suggests a link, but robust causal relationships remain unexplored.
• Mendelian randomization (MR) has not been applied to investigate metabolite-Charcot foot associations.

Purpose of the Study:

• To investigate the causal relationships between genetically predicted metabolite levels and Charcot foot risk.
• To identify specific metabolites that may act as protective or risk factors for Charcot foot.
• To explore the potential of metabolites as therapeutic biomarkers for Charcot foot.

Main Methods:

• Utilized summary statistics from Genome-wide Association Studies (GWAS) for 1400 metabolites.
• Employed Mendelian randomization (MR) analysis, primarily using the inverse variance weighted (IVW) method.
• Conducted sensitivity analyses including Bayesian weighted MR, constrained maximum likelihood, contamination mixture, RAPS, deIVW, and colocalization to ensure result validity and robustness.

Main Results:

• Identified hexadecenedioate (C16:1-DC), octadecadienedioate (C18:2-DC), and octadecanedioylcarnitine (C18-DC) as having protective causal relationships with Charcot foot.
• Colocalization analysis confirmed shared causal variants for these three metabolites and Charcot foot.
• Sixty-four additional metabolites showed suggestive associations, with 25 positively and 33 negatively correlated with Charcot foot risk. Sensitivity analyses supported the primary findings, with no significant heterogeneity or horizontal pleiotropy after FDR correction.

Conclusions:

• This MR study identified specific protective and risk metabolites associated with Charcot foot.
• Metabolite levels can be modulated, suggesting potential therapeutic strategies.
• These identified metabolites represent novel biomarkers for Charcot foot therapy and risk reduction.