Metabolites and coronary heart disease: A two sample Mendelian randomization

Area of Science:

• Cardiovascular Disease Epidemiology
• Metabolomics
• Genetic Epidemiology

Background:

• Observational studies suggest links between circulating metabolites and coronary heart disease (CHD).
• The causal relationship between these metabolites and CHD remains unclear.
• This study aimed to clarify the bidirectional causal relationship and protective factors.

Purpose of the Study:

• To determine the bidirectional causal relationship between circulating metabolites and CHD.
• To identify specific circulating metabolites associated with decreased CHD risk.

Main Methods:

• A two-sample Mendelian randomization (MR) study design was employed.
• Genome-wide association study (GWAS) data for metabolites (n=24,925) and CHD (n=86,995) were utilized.
• Inverse variance weighted meta-analysis, median weighting, MR Egger, and MR-PRESSO were used for analysis.

Main Results:

• Positive associations with CHD risk were found for free cholesterol in large LDL, total cholesterol in medium LDL and LDL, phospholipids in medium LDL, and various metabolites in small VLDL and small HDL, including triglycerides, free cholesterol, and phospholipids.
• Alanine also showed a positive association with CHD risk.
• Phospholipids in medium HDL were negatively associated with CHD, suggesting a protective effect.

Conclusions:

• Mendelian randomization analysis indicated a protective effect of phospholipids in medium HDL against CHD.
• Conversely, several metabolites including free cholesterol and total cholesterol in LDL and VLDL, phospholipids in LDL, triglycerides in VLDL and HDL, and alanine were associated with increased CHD risk.
• Further research is needed to translate these findings into clinical practice.