Abstract
Coronary heart disease (CHD) represents a significant health risk for humans. The impact of regular skimmed milk consumption on the risk of CHD, and the role of serum metabolites in mediating the effect of skimmed milk on CHD remain inconclusive. the present study is based on an open-source metabolomic investigation of serum metabolites. the analysis employed 2-step, two-sample Mendelian randomization and multi-response MR in conjunction with meta-analysis to estimate the overall impact of skimmed milk on the risk of CHD. furthermore, mediation analysis was employed in this study to ascertain the mediating role of serum metabolites between skimmed milk consumption and the risk of CHD. co-localization analysis was used to explore in-depth associations between skimmed milk and CHD. The results of the meta-analysis indicated that there was an elevated risk of CHD with each standard deviation increase in skimmed milk intake (OR = 3.628; 95% CI, 1.386-9.500; P = .009). In addition, 5 serum metabolites were found to be causally associated with CHD (FDR-P < .05). Following the application of co-correction by multi-response MR, two-sample Mendelian randomization and mediator analysis, a single serum metabolite was identified as exhibiting a positive causal relationship with CHD, namely benzoate to oleoyl-linoleoyl-glycerol (18:1-18:2) [2] ratio. It is worthy of note that the moderating effect of this metabolite on the causal relationship between skimmed milk and CHD is fully mediating effect. Furthermore, our co-localization analysis revealed that long-term consumption of skimmed milk and CHD were concurrently regulated by 2 SNPs, specifically rs4970834 and rs7528419. In total, 6 genes on this chromosome are affected by this phenomenon: KIAA1324, SARS, CELSR2, PSRC1, MYBPHL, and SORT1. Ultimately, through the utilization of summary-data-based Mendelian randomization analyses, it was determined that skimmed milk, circulating metabolites, and CHD exhibit shared potential drug targets within the coronary arteries, namely HLA-DRB1, and TRPC4AP (FDR-P < .05, P-HEIDI > 0.05). The present study demonstrates that the consumption of skimmed milk is positively associated with the incidence of CHD. Furthermore, the findings indicate that a serum metabolite - benzoate to oleoyl-linoleoyl-glycerol (18:1-18:2) [2] ratio - plays a fully mediating role in this association. Combined with summary-data-based Mendelian randomization analysis, we suggest that HLA-DRB1 and TRPC4AP may be potential therapeutic targets for CHD.