Exploring causal pathways between hypertension, lipid levels, and gout: Insights from Mendelian randomization and...

Gout, a common form of inflammatory arthritis, is caused by the deposition of monosodium urate crystals in joints and soft tissues. While associations between hypertension, lipid levels, and gout have been explored, their causal relationships remain unclear. This study aimed to examine the causal effects of hypertension and lipid levels on gout using multivariable Mendelian randomization (MR) and observational data from the National Health and Nutrition Examination Survey. We combined data from National Health and Nutrition Examination Survey (2006-2016) and genetic information from genome-wide association studies to investigate the associations between hypertension, lipid levels (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides (TG), and total cholesterol), and gout. A 2-sample MR analysis was conducted using genetic instruments from genome-wide association studies and FinnGen datasets to determine the causal effects of hypertension and lipid levels on gout. In addition, multivariate Mendelian randomization was employed to simultaneously assess the causal impacts of multiple lipid traits and hypertension on gout. Sensitivity analyses were performed to assess the robustness of the findings. Observational analyses demonstrated a strong positive association between hypertension and gout risk (odds ratio [OR] = 5.35, 95% confidence interval [CI]: 4.45-6.37, P < .001). MR analysis further confirmed a causal relationship between hypertension (inverse variance weighting [IVW] OR = 2.68, 95% CI: 1.60-4.49, P < .001), TG (IVW OR = 1.37, 95% CI: 1.20-1.56, P < .001), low-density lipoprotein cholesterol (IVW OR = 1.34, 95% CI: 1.18-1.54, P < .001), and gout risk. Multivariate Mendelian randomization analysis indicated that while TG showed a significant causal effect on gout, hypertension and other lipid traits did not exhibit significant causal relationships in the multivariate framework. Sensitivity analyses affirmed the consistency and reliability of these findings. This study provides robust evidence for a significant causal relationship between hypertension, lipid levels, and gout, with TG emerging as a key factor in gout pathogenesis. These findings suggest that targeting hypertension and dyslipidemia, particularly TG, may serve as important strategies for the prevention and management of gout. Further research into the underlying biological pathways could offer new insights into gout pathogenesis and potential therapeutic interventions.