Abstract
BackgroundStudies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR).Methods and findingsWe used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 μmol/l] increase in SU: −1.99 ml/min/1.73 m2; 95% CI −2.86 to −1.11; P = 8.08 × 10−6; odds ratio [OR] for CKD: 1.48; 95% CI 1.32 to 1.65; P = 1.52 × 10−11). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10−3), which served as a positive control of our approach. Overall, our MR analysis had >99% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study.ConclusionsEvidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.
Highlights
10% of the global population has chronic kidney disease (CKD) [1,2], which can result in end-stage renal disease, associated with shortened life expectancy and requirement for dialysis or kidney transplantation [3]
Evidence from our series of causal inference approaches using genetics does not support a causal effect of serum urate (SU) level on estimated glomerular filtration rate (eGFR) level or CKD risk
We examined 26 single nucleotide variant (SNV) strongly associated with SU level identified in a genome-wide association (GWA) meta-analysis study of 110,347 participants of European ancestry conducted by the Global Urate Genetics Consortium (S1 Table) [14]
Summary
10% of the global population has chronic kidney disease (CKD) [1,2], which can result in end-stage renal disease, associated with shortened life expectancy and requirement for dialysis or kidney transplantation [3]. Observational studies have consistently shown strong positive associations between serum urate (SU) levels and the risk of CKD [4,5]; whether the relation is causal remains unknown. Findings in inducedhyperuricemia rodent models have suggested a causal role of urate in hypertension and associated renal pathophysiology [9]. These findings are difficult to directly translate to humans as rodents have considerably lower urate levels owing to functional uricase [9]. Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR).
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