Uric Acid and Cardiovascular Events: A Mendelian... : Journal of the American Society of Nephrology (original) (raw)

Clinical Research

A Mendelian Randomization Study

Kleber, Marcus E.*; Delgado, Graciela*; Grammer, Tanja B.*; Silbernagel, Günther†; Huang, Jie‡; Krämer, Bernhard K.*; Ritz, Eberhard§; März, Winfried*,‖,¶

*Fifth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany;

†Department of Angiology, Swiss Cardiovascular Center, Inselspital, University of Bern, Bern, Switzerland;

‡Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom;

§Division of Nephrology, Department of Medicine, University Hospital Heidelberg, Heidelberg, Germany;

‖Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; and

¶Synlab Academy, Synlab Services GmbH, Mannheim, Germany

Correspondence: Dr. Marcus E. Kleber, Fifth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. Email: [email protected]

Received July 10, 2014

Accepted December 24, 2014

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.