Sphingomyelins are potential biomarkers of low atherogenic sdLDL/LDL ratio: findings from a cross-sectional metabolomic study

Small dense low-density lipoprotein (sdLDL) is a highly atherogenic LDL subfraction that confers cardiovascular risk beyond total LDL cholesterol. However, its routine clinical assessment remains limited. Metabolomics offers an opportunity to identify metabolic signatures linked to sdLDL burden and uncover novel biomarkers of atherogenic dyslipidemia. A cross-sectional metabolomics analysis was conducted among 2,833 participants from the Qatar Biobank. Serum metabolites were quantified using untargeted high-resolution mass spectrometry. sdLDL and LDL cholesterol were estimated using Sampson’s equations, and the sdLDL/LDL ratio was used as a normalized marker of LDL particle quality. Multivariate orthogonal partial least-squares modeling, adjusted linear regression, pathway enrichment, and correlation analyses were performed. The robustness and reproducibility of the identified associations were evaluated through internal validation in randomly assigned discovery and validation cohorts, complemented by sensitivity and sex-stratified analyses. Sphingomyelins emerged as the predominant and most consistent metabolite class inversely associated with the sdLDL/LDL ratio. Higher sphingomyelin levels correlated with improved insulin sensitivity, lower triglycerides, reduced atherogenic index of plasma, and favorable hormonal profiles. These findings underscore the complexity of sphingomyelin biology and suggest that circulating sphingomyelins may be linked to a more favorable lipoprotein phenotype; they merit further evaluation as candidate biomarkers in prospective studies.