Association between serum urate levels, gout and breast cancer: observational and Mendelian randomization analyses.

Abstract

Background: It is hypothesized that uric acid acts as an antioxidant and may prevent cancer. However, observational studies regarding the relationship between serum urate levels, gout, and breast cancer have provided discrepant evidence. Therefore, the objective of our study was to investigate the potential causal relationship between them.

Methods: This study included 12,451 participants from the National Health and Nutrition Examination Survey (NHANES) 2009-2018. Associations between urate levels, gout, and breast cancer were examined using multivariate logistic regression analysis. In addition, to assess the causal link among them, Mendelian randomization (MR) analysis was conducted, primarily using the inverse variance weighted (IVW) approach, supplemented by MR Egger and weighted median approaches, and a set of sensitivity analyses to test the robustness of the results, and finally, multivariate MR was used to adjust for confounders.

Results: In cross-sectional studies, urate levels [odds ratio (OR) 0.99, 95% confidence interval (CI): 0.89-1.09, P=0.80] and gout (OR 0.96, 95% CI: 0.53-1.76, P=0.90) were negatively associated with breast cancer risk after controlling for multiple confounders, although the P value was not significant. Two-sample MR analysis showed that serum urate levels were negatively associated with the estrogen receptor-negative (ER-) breast cancer (IVW, OR 0.916, 95% CI: 0.848-0.989, P=0.03) risk, but not significantly associated with overall and the estrogen receptor-positive (ER+) breast cancer (IVW, both P>0.05). In addition, gout was negatively associated with overall (IVW, OR 0.07, 95% CI: 0.008-0.594, P=0.02), ER+ (IVW, OR 0.062, 95% CI: 0.005-0.742, P=0.03), and ER- breast cancer (IVW, OR 0.041, 95% CI: 0.004-0.472, P=0.01) risk. These associations persisted after multivariate MR adjustment for smoking status, alcohol intake frequency, and body mass index (BMI).

Conclusions: Our study elucidated the relationship between uric acid, gout and breast cancer, and further studies are still needed in the future to clarify the mechanisms involved.