Elevated Uric Acid Mediates the Effect of Obesity on Hypertension Development: A Causal Mediation Analysis in a Prospective Longitudinal Study

Objective: Although elevated uric acid is associated with obesity and considered a predictor of hypertension, the causal linkage between the three metabolic conditions is not very clear. We aim to examine whether elevated uric acid mediates the effects of obesity on hypertension development. Methods: A total of 1984 participants (mean aged 53 years, 62.10% female) with repeated measurements of obesity, blood pressure, and uric acid 4 years apart in the Gusu cohort were included. We first applied cross-lagged panel analysis and bidirectional association analysis to delineate the temporal association between obesity and hyperuricemia. Then, a causal mediation model was constructed to further examine the causal role of hyperuricemia in the linkage between obesity and hypertension. Age, sex, education, cigarette smoking, alcohol consumption, fasting blood glucose, and lipids were adjusted. Results: The cross-lagged panel analysis demonstrated that the relationship from baseline obesity to follow-up hyperuricemia was stronger than that from baseline hyperuricemia to follow-up obesity (β: 0.09 vs 0.06, P < 0.01 for BMI, β: 0.13 vs 0.07, P < 0.01 for WC). Bidirectional association analysis found that baseline obesity predicted the risk of incident hyperuricemia (OR = 1.09, P < 0.01 for BMI, OR = 1.05, P < 0.01 for WC), but the other directional association was not statistically significant (all P > 0.05). The causal mediation analysis found that hyperuricemia partially mediated the association of baseline BMI (mediate proportion: 3.09%, 95% CI: 0.97%∼ 6.00% for SBP, 3.74%, 95% CI: 1.55%∼ 7.00% for DBP) and baseline WC (mediate proportion: 5.56%, 95% CI: 2.01%∼ 11.00% for SBP, 5.81%, 95% CI: 2.59%∼ 10.00% for DBP) with follow-up blood pressures. Conclusion: Obesity preceded hyperuricemia and the latter partially mediated the relationship between obesity and hypertension, independent of behavioral and other metabolic factors.