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Uric Acid and Cardiovascular Events: A Mendelian Randomization Study.

ABSTRACT: Obesity and diets rich in uric acid-raising components appear to account for the increased prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension, diabetes mellitus, CKD, and cardiovascular disease are also increasing. We used Mendelian randomization to examine whether uric acid is an independent and causal cardiovascular risk factor. Serum uric acid was measured in 3315 patients of the Ludwigshafen Risk and Cardiovascular Health Study. We calculated a weighted genetic risk score (GRS) for uric acid concentration based on eight uric acid-regulating single nucleotide polymorphisms. Causal odds ratios and causal hazard ratios (HRs) were calculated using a two-stage regression estimate with the GRS as the instrumental variable to examine associations with cardiometabolic phenotypes (cross-sectional) and mortality (prospectively) by logistic regression and Cox regression, respectively. Our GRS was not consistently associated with any biochemical marker except for uric acid, arguing against pleiotropy. Uric acid was associated with a range of prevalent diseases, including coronary artery disease. Uric acid and the GRS were both associated with cardiovascular death and sudden cardiac death. In a multivariate model adjusted for factors including medication, causal HRs corresponding to each 1-mg/dl increase in genetically predicted uric acid concentration were significant for cardiovascular death (HR, 1.77; 95% confidence interval, 1.12 to 2.81) and sudden cardiac death (HR, 2.41; 95% confidence interval, 1.16 to 5.00). These results suggest that high uric acid is causally related to adverse cardiovascular outcomes, especially sudden cardiac death.

SUBMITTER: Kleber ME

PROVIDER: S-EPMC4625666 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Uric Acid and Cardiovascular Events: A Mendelian Randomization Study.

Kleber Marcus E ME Delgado Graciela G Grammer Tanja B TB Silbernagel Günther G Huang Jie J Krämer Bernhard K BK Ritz Eberhard E März Winfried W

Journal of the American Society of Nephrology : JASN 20150318 11

Obesity and diets rich in uric acid-raising components appear to account for the increased prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension, diabetes mellitus, CKD, and cardiovascular disease are also increasing. We used Mendelian randomization to examine whether uric acid is an independent and causal cardiovascular risk factor. Serum uric acid was measured in 3315 patients of the Ludwigshafen Risk and Cardiovascular Health Study. We calculated a weighted ...[more]

PMID: 25788527

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Project description:AimsSerum uric acid (SUA) levels have been previously linked to a higher risk of cardiovascular disease (CVD) in individuals with type 2 diabetes (T2D) according to various observational studies. However, whether this association is causally linked or simply influenced by confounding factors is unclear. Therefore, this study utilized Mendelian randomization (MR) analysis to explore the causality between SUA levels and the risk of CVD in individuals with T2D.MethodsOur study cohort consisted of 5723 participants who were diagnosed with T2D in the National Health and Nutrition Examination Survey (NHANES) from 1999-2018. The study assessed the association between SUA levels and the risk of CVD using a multivariable logistic regression model. To further examine causality between SUA levels and CVD, a two-sample MR study was conducted utilizing genetic data from genome-wide association studies (GWAS) involving over 140,000 individuals. The main MR analysis employed the inverse-variance-weighted (IVW) method. Additionally, several sensitivity analyses were performed to evaluate the robustness and pleiotropy of the results.ResultsIn the cross-sectional study, after multivariable adjustment, participants with SUA levels >6.7 mg/dL exhibited odds ratios (ORs) of 1.51 (95% CI: 1.01-2.26, p=0.049) for heart failure, 1.02 (95% CI: 0.69-1.50, p=0.937) for coronary heart disease, 1.36 (95% CI: 0.78-2.38, p=0.285) for angina, and 1.22 (95% CI: 0.80-1.85, p=0.355) for myocardial infarction when compared to participants with SUA levels ≤ 4.6 mg/dL. However, in the IVW analysis, no causality between SUA levels and the risk of heart failure was observed (OR = 1.03, 95% CI: 0.97-1.09, p = 0.293). The secondary analysis yielded similar results (OR = 1.05, 95% CI: 0.96-1.14, p = 0.299). The sensitivity analyses further supported our primary findings.ConclusionBased on the MR study, we did not find supporting evidence for a causal association between SUA levels and the risk of heart failure.

Dataset Information

Uric Acid and Cardiovascular Events: A Mendelian Randomization Study.

Publications

Uric Acid and Cardiovascular Events: A Mendelian Randomization Study.

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