Plasma Metabolites of Kynurenine Pathway and Risk of Stroke in the General Population: A Nested Case-control Study

Kynurenine pathway has been linked to several cardiovascular diseases, but their specific associations with stroke risk remain elusive. This study aimed to explore the associations between kynurenine pathway metabolites and the subsequent risk of stroke. A case-control study nested in a community-based cohort (n = 16,113) was performed between 2013 and 2018. A total of 412 incident stroke cases and 412 controls matched by age and sex were included. Plasma levels of kynurenine pathway metabolites, including tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (3-HK), 3-hydroxy anthranilic acid (3-HAA), anthranilic acid (AA), and xanthurenic acid (XA), were measured by ultrahigh performance liquid chromatography-tandem mass spectrometry. Conditional logistic regression analyses were used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs) between these biomarkers and stroke risk. After adjustment for body mass index, current smoking, marital status, estimated glomerular filtration rate, and physical activity, the corresponding OR for the highest versus lowest quintile of XA was 0.56 (95% CI: 0.36-0.89, P trend = 0.018) for total stroke risk and 0.48 (95% CI:0.28-0.81, P trend = 0.015) for ischemic stroke risk, respectively. No significant association was observed between plasma tryptophan, kynurenine, KA, 3-HK, 3-HAA, or AA and stroke risk. Our novel findings indicate an inverse association of plasma XA with the risk of total stroke and ischemic stroke in the general population. These findings highlight the potential of plasma XA as a valuable biomarker for assessing stroke risk and developing targeted prevention strategies.