Abstract
N-lactoyl-amino acids (Lac-AA) are emerging as important metabolites with diverse physiological roles. This study integrates metabolomics and genomics to investigate the genetic determinants and clinical relevance of three Lac-AA: N-Lactoyl phenylalanine (Lac-Phe), N-Lactoyl tyrosine (Lac-Tyr), and N-Lactoyl valine (Lac-Tyr). We conducted a metabolome-wide association study (mGWAS) on 2811 participants followed by a phenome-wide association study (PheWAS) and pathway enrichment analysis. Our mGWAS revealed modest genetic contributions to Lac-AA levels, with genome-wide significant loci identified for Lac-Tyr and Lac-Val, but not for Lac-Phe. PheWAS analysis linked these genetic variants to key clinical traits, including white blood cell count, platelet count, and glucose levels. Pathway enrichment highlighted the involvement of Lac-AA in immune-metabolic crosstalk, particularly in inflammation and energy metabolism. These findings suggest that Lac-AA levels are primarily influenced by dynamic metabolic or inflammatory states rather than fixed genetic factors. Our results underscore the potential of Lac-AA as metabolic sensors and biomarkers at the intersection of cellular energy states and systemic inflammation, opening new avenues for research in metabolic and inflammatory disorders.