The uric acid-to-homocysteine ratio as a prognostic marker for all-cause and cardiovascular mortality: A national population-based study

Abstract

The homocysteine (Hcy) paradox, the failure of Hcy-lowering therapies to consistently reduce cardiovascular events, remains a major challenge in metabolic medicine. We hypothesize that adenosine (Ado), a stoichiometric byproduct of Hcy production with vascular protective effects, may be relevant to this paradox. Because circulating Ado is difficult to measure at scale, uric acid (UA) is a downstream end product of adenosine catabolism, we evaluated the UA-to-Hcy ratio as an exploratory composite index that may capture aspects of Hcy-related purine/adenosine metabolism. A nationally representative, population-based prospective cohort study. Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 1999-2006 cycles, including 17,180 participants for all-cause and 14,667 participants for cardiovascular mortality. Survey-weighted Cox models estimated hazard ratios (HRs) for mortality. Restricted cubic splines (RCS) assessed non-linearity, time-dependent receiver operating characteristic curves (timeROC) evaluated predictive performance, and generalized additive models (GAMs) examined associations between B-vitamins and the UA-to-Hcy ratio. The UA-to-Hcy ratio was inversely associated with all-cause mortality (HR = 0.989 per unit increase; 95% CI, 0.986-0.993) and cardiovascular mortality (HR = 0.987 per unit increase; 95% CI, 0.980-0.995), exhibiting nonlinear relationships ( P < 0.001). The ratio showed moderate discriminatory performance, with the highest AUCs observed for 5-year all-cause mortality (AUC = 0.691, 95% CI: 0.666-0.716) and cardiovascular mortality (AUC = 0.712, 95% CI: 0.677-0.749). Additionally, vitamin B12 and folate showed an inverted L-shaped association with the ratio ( P < 0.001), indicating a saturation effect in their ability to modulate this metabolic balance. The UA-to-Hcy ratio was independently associated with all-cause and cardiovascular mortality and showed stable discriminatory performance for mortality prediction in this cohort. Together with the observed B-vitamin saturation pattern, these findings warrant further investigation of Hcy-related purine/adenosine metabolism as a potential contributor to cardiovascular risk.