A Multi-Cohort Metabolomics Analysis Discloses Sphingomyelin (32:1) Levels to be Inversely Related to Incident Ischemic Stroke

Background and Purpose: To search for novel pathophysiological pathways related to ischemic stroke using a metabolomics approach. Methods: We identified 204 metabolites in plasma by liquid chromatography mass spectrometry in 3 independent population-based samples (TwinGene, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) and Uppsala Longitudinal Study of Adult Men). TwinGene was used for discovery and the other 2 samples were meta-analyzed as replication. In PIVUS, traditional cardiovascular (CV) risk factors, multiple markers of subclinical CV disease, markers of coagulation/fibrinolysis were measured and analyzed in relation to top metabolites. Results: In TwinGene (177 incident cases, median follow-up 4.3 years), levels of 28 metabolites were associated with incident ischemic stroke at a false discover rate (FDR) of 5%. In the replication (together 194 incident cases, follow-up 10 and 12 years, respectively), only sphingomyelin (32:1) was significantly associated (HR.69 per SD change, 95% CI.57-0.83, P value = .00014; FDR <5%) when adjusted for systolic blood pressure, diabetes, smoking, low density lipoportein (LDL)- and high density lipoprotein (HDL), body mass index (BMI) and atrial fibrillation. In PIVUS, sphingomyelin (32:1) levels were significantly related to both LDL- and HDL-cholesterol in a positive fashion, and to serum triglycerides, BMI and diabetes in a negative fashion. Furthermore, sphingomyelin (32:1) levels were related to vasodilation in the forearm resistance vessels, and inversely to leukocyte count (P < .0069 and .0026, respectively). Conclusions: An inverse relationship between sphingomyelin (32:1) and incident ischemic stroke was identified, replicated, and characterized. A possible protective role for sphingomyelins in stroke development has to be further investigated in additional experimental and clinical studies.