POS1478-HPR GENETIC LIABILITY TO URATE LEVELS IN RELATION TO CARDIOVASCULAR DISEASES: A MENDELIAN RANDOMISATION STUDY

Abstract

Background:

Accumulating evidence has linked elevated urate levels to the pathogenesis of major cardiovascular diseases (CVDs) [1]. Several previous studies have suggested that genetically predicted higher serum urate levels are associated with a high risk of peripheral artery disease (PAD) and stroke. However, the relationships between urate levels and other CVD phenotypes remain unclear. To address these issues, we apply Mendelian Randomization (MR), a more robust method that leverages genetic variants as instrumental variables to assess causality between an exposure and outcome. MR minimizes the risks of reverse causation and confounding, making it particularly suitable for determining the causal relationship [3].

Objectives:

To mitigate potential biases in causal estimates, we adopted the Latent Heritable Confounder MR (LHC-MR) method to estimate both the bi-directional causal effects between urate levels and six CVDs (i.e., atrial fibrillation [AF], coronary artery disease [CAD], venous thromboembolism [VTE], heart failure [HF], PAD, and Stroke).

Methods:

We utilized the most recent and largest publicly available genome-wide association study (GWAS) summary statistics from European ancestry individuals of urate from 288,649 individuals and the largest GWAS summary statistics of six CVDs comprising AF (N = 1,030,836), CAD (N = 1,165,690), VTE (N =1,500,861), HF (N = 977,323), PAD (N = 511,634), and Stroke (N = 1,308,460). The LHC-MR method was employed to explore potential causal relationships between urate levels and six major CVDs. LHC-MR utilizes summary statistics from GWAS and genetic variation to investigate bidirectional causal effects between complex traits [4]. Unlike traditional Mendelian randomization methods, LHC-MR enhances the ability to estimate both direct and indirect genetic effects, as well as confounding influences, while accounting for sample overlap. To assess the causal relationship between urate levels and CVDs, we applied a Bonferroni correction with a threshold of P < 4.17×10⁻³, adjusting for multiple tests. A unidirectional causal relationship was confirmed when the P-value in one direction was below this threshold, while the opposite direction had a P-value > 0.05. A bidirectional causal relationship was considered when P-values in both directions were below the threshold of 4.17×10^-3.

Results:

Our results show that genetically elevated urate levels are most strongly associated with an increased risk of CAD, with an odds ratio (OR) of 1.21 (95% CI=1.11-1.32). This indicates that each 1-SD increase in genetically predicted urate levels corresponds to a 21% higher likelihood of developing CAD (Figure 1). Similarly, for PAD, a 1-SD increase in urate levels was associated with a 12% higher risk (OR = 1.12, 95% CI=1.04-1.20). However, no significant causal associations were found between urate levels and the remaining four CVDs. Additionally, there was no evidence of a reverse causal relationship between urate levels and any of the six CVDs. The observed relationship between elevated urate levels and CAD or PAD may be attributed to several mechanisms. It has been hypothesized that urate induces oxidative stress by activating NADPH oxidase following urate uptake by target cells or promotes cardiovascular disease progression via heme enzyme myeloperoxidase (MPO)-mediated pathways. Furthermore, elevated uric acid levels can activate calcineurin-1 and induce endoplasmic reticulum (ER) stress or ROS-dependent endothelin-1 (ET-1) pathways,contributing to significant cardiomyocyte apoptosis, interstitial fibrosis, diastolic dysfunction, and ventricular remodeling, accelerating the onset and progression of CAD and PAD.

Conclusion:

Overall, our findings support that elevated urate concentrations have a detrimental effect on CVDs, particularly evident for CAD and PAD, suggesting that urate could serve as a reliable predictor of cardiovascular risk. Although the underlying mechanism remains unclear, considering urate in the assessment of cardiovascular risk could be valuable, and it may represent a potential target for reducing cardiovascular events. High-quality trials are necessary to provide definitive evidence on the specific clinical contexts in which urate-lowering interventions may benefit cardiovascular health.

REFERENCES:

[1] Sharaf El Din U.A.A., Salem M.M., Abdulazim D.O. Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: A review. J Adv Res, 2017, 8, 537-48. [2] Gill D., Cameron A.C., Burgess S., et al. Urate, Blood Pressure, and Cardiovascular Disease: Evidence From Mendelian Randomization and Meta-Analysis of Clinical Trials. Hypertension, 2021, 77, 383-92. [3] Birney E. Mendelian Randomization. Cold Spring Harb Perspect Med. 2022;12(4):a041302. [4] Darrous, L., Mounier, N. & Kutalik, Z. Simultaneous estimation of bi-directional causal effects and heritable confounding from GWAS summary statistics. Nat. Commun. 12, 1–15 (2021). [5] Kleber ME, Delgado G, Grammer TB, Silbernagel G, Huang J, Krämer BK, Ritz E, März W. Uric acid and cardiovascular events: a Mendelian randomization study. J Am Soc Nephrol2015; 26:2831–2838. Figure 1The causal inference between urate levels and six cardiovascular diseases.Forest plot of the LHC-MR analysis on the association between urate levels and six CVDs. Circles represent the odd ratio (OR) estimate and the error bars indicate the 95% confidence interval. The left panel represents the estimated causal effect of urate levels on CVDs, while the right panel represents the estimated causal effect of CVDs on urate levels. A positive association is indicated by OR > 1, while a negative association is indicated by OR < 1. Atrial fibrillation; CAD, Coronary artery disease; VTE, Venous thromboembolism; HF, Heart failure; PAD, Peripheral artery disease.

Acknowledgements:

This work was financially supported by the National innovation and EntrepreneurshipTraining Program for College Students, China (20240423).

Disclosure of Interests:

None declared. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.