Evaluation of the causal effects of blood lipid levels on gout with summary level GWAS data: two-sample Mendelian randomization and mediation analysis

Objective Many observational studies have identified that gout patients are often comorbid with dyslipidemia, which is typically characterized by a decrease in high-density lipoprotein cholesterol (HDL) and an increase in triglycerides (TG). However, the relationship between dyslipidemia and gout is still unclear. Methods We first performed a two-sample Mendelian randomization (MR) to evaluate the causal effect of four lipid traits on gout and serum urate based on summary association statistics available from large scale genome-wide association studies (up to ∼100,000 for lipid, 69,374 for gout and 110,347 for serum urate). We adopted multivariable Mendelian randomization to estimate the causal effect independently. We also assessed the mediated effect by serum urate between lipids and gout with a mediation analysis. The MR results were validated with extensive sensitive analyses. Results Genetically lower HDL was positively associated with the risk of gout and serum urate concentration. Each standard deviation (SD) (∼12.26 mg/dL) increase was genetically associated with an odds ratio of gout of 0.75 (95% CI 0.62 ∼ 0.91, p = 3.31E-3) and with a 0.09 mg/dL (95% CI: -0.12 ∼ -0.05, p = 7.00E-04) decrease in serum urate concentration. Genetically higher TG was positively associated with the serum urate concentration. Each SD (∼112.33 mg/dL) increase was genetically associated with a 0.10 mg/dL (95% CI: 0.06 ∼ 0.14, p = 9.87E-05) increase in serum urate concentration. Those results were robust against various sensitive analyses. In addition, the multivariable Mendelian randomization confirmed the independent effect of HDL and TG on the gout/serum urate after adjustment for the other lipids. Finally, the mediation analysis showed that both HDL and TG could indirectly affect gout morbidity via the pathway of serum urate. The mediation effect accounted for about 13.0% or 28.0% of the total effect of HDL and TG, respectively. Conclusion Our study confirmed the causal associations between HDL/TG and gout/serum urate. Furthermore, the effect of HDL or TG on gout could also be mediated by serum urate. Key Messages Epidemiological studies have identified an accompanying association between lipid and gout. However, whether the association is causal is unclear. Mendelian randomization with genetic variants as instrumental variables is a useful tool facilitate the validation of a causal relationship for modifiable risk factors. The direct and indirect effects of lipids on gout, controlling for the serum urate concentration, can be estimated by a mediation analysis with serum urate serving as a mediator. We confirmed that elevated HDL levels can directly and indirectly lead to the decreased risk of gout, whereas elevation of TG levels can directly and indirectly elevate the risk of gout.