Plasma Tryptophan Hydroxylase 1 Activity-related Metabolic Markers and Stroke Risk: A Nested Case-control Study.

Tryptophan hydroxylase 1 (TPH1) has emerged as a therapeutic target for metabolic diseases, but its association with stroke in the general population remains unclear. This study investigated the relationship between TPH1-related metabolic markers and stroke risk. A nested case–control study was conducted within a community-based cohort in China (n = 16,113; 2013–2018), including 412 incident stroke cases and 412 controls matched on age and sex. Plasma levels of tryptophan (Trp), kynurenine (Kyn), and 5-hydroxyindoleacetic acid (5-HIAA) were quantified via ultrahigh-performance liquid chromatography-tandem mass spectrometry. The ratios of 5-HIAA/Trp (as a proxy of TPH1 activity) and 5-HIAA/Kyn were calculated. Conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Higher plasma 5-HIAA/Trp and 5-HIAA/Kyn ratios were significantly associated with an increased risk of total stroke. The corresponding ORs for the highest versus lowest quartile were 2.12 (95% CI: 1.27–3.56, P for trend = 0.003) and 1.90 (95% CI: 1.21–3.00, P for trend = 0.003), respectively. Similar associations were observed for ischemic stroke, with ORs of 2.24 (95% CI: 1.29–3.91, P for trend = 0.004) and 2.11 (95% CI: 1.25–3.56, P for trend = 0.004), respectively. Plasma 5-HIAA levels alone were also positively associated with the risk of total stroke (OR = 1.46, 95% CI: 0.91–2.36, P for trend = 0.044). This study provides the first epidemiological evidence that the 5-HIAA/Trp ratio and 5-HIAA/Kyn ratio are positively associated with the risk of both total and ischemic stroke in the general population. These findings highlight the potential of these ratios as potential biomarkers for stroke risk assessment and TPH1-related metabolism as promising targets for preventive interventions.