Causal relationship between genetically determined plasma metabolites and stroke: A two sample Mendelian randomization study

This study investigates the causal relationship between plasma metabolites and stroke. The primary analytical approach employed was the inverse variance weighted (IVW) method, complemented by the weighted median (WM) and MR Egger methods for Additionally, validation of the identified plasma metabolites was performed using the Steiger test and LD linkage disequilibrium score. Furthermore, the main results were confirmed through data from the UK Biobank. The IVW analysis revealed the most notable negative association found in X-17335 levels (OR [95 % CI]: 0.82 [0.72, 0.94]). On the other hand, the strongest positive effect was seen in the 5′-homophase (AMP) to phase ratio (OR [95 % CI]: 1.17 [1.03, 1.32]). Moving on to the validation dataset, the most significant positive effect was observed in the 13 HODE+9-HODE levels (OR [95 % CI]: 0.996 [0.993, 0.999]), whereas the most significant negative effect was seen in the Dihydroxide levels (OR [95 % CI]: 1.004 [1.00, 1.007]). Notably, Alpha ketoglutarate levels exhibited strong causal effects in both datasets (OR 0.908 [0.841, 0.981], p = 0.0144). Enrichment analysis highlighted the association of Alpha ketoglutarate levels with five plasma metabolites in metabolic pathways relevant to stroke, specifically Arginine biosynthesis, Butanoate metabolism, Citrate cycle (TCA cycle), Alanine, aspartate, and glutamate metabolism, and Lipid acid metabolism, all linked to oxoglutaric acid. The discovery dataset showed the most significant positive effect of the 5′-homophase (AMP) to phase ratio, while the validation dataset revealed the most significant positive effect of the 13 HODE+9-HODE levels. Additionally, alpha ketoglutarate may offer a potential protective effect on stroke by influencing five metabolic pathways that intersect with Oxoglutaric acid during the progression of the condition.