Caffeine metabolic phenotypes and hypertension risk: Urinary paraxanthine-to-caffeine ratio threshold and mediating...

This study aimed to resolve the caffeine-hypertension paradox by investigating the association between urinary paraxanthine-to-caffeine molar ratio (PMR)-a functional biomarker of CYP1A2 metabolic capacity-and hypertension risk, while exploring mediation by serum uric acid (SUA) and white blood cells (WBC).

Using nationally representative NHANES data (2009-2014; n = 1611), urinary PMR was quantified via UPLC-ESI-MS/MS. Hypertension was defined per AHA/ACC 2017 guidelines. Multivariable logistic regression analyzed PMR-hypertension associations (unadjusted, age/sex-adjusted, fully adjusted). Dose-response relationships were modeled using restricted cubic spline (RCS) analysis. Causal mediation tested SUA/WBC pathways. Faster caffeine metabolism (higher PMR) demonstrated a nonlinear inverse relationship with hypertension. A critical inflection point at PMR = 3.03 revealed: slow metabolizers (PMR <3.03) had 51 % higher hypertension risk than fast metabolizers (OR = 0.49, 95 % CI: 0.40-0.60; P < 0.001). SUA and WBC collectively mediated 12 % of PMR's protective effect (SUA: 8.0 %; WBC: 4.0 %). Subgroup analyses showed effect modification by age and race (P interaction <0.05).

PMR serves as a novel biomarker clarifying the caffeine-hypertension paradox: fast metabolizers (PMR ≥3.03) exhibit significantly reduced hypertension risk, partially mediated by reduced SUA and inflammation. This supports personalized caffeine intake recommendations based on metabolic phenotype.