Assessing the Relationship Between Serum Urate and Urolithiasis Using Mendelian Randomization: An Analysis of the UK Biobank.

Abstract

RATIONALE AND OBJECTIVE\nThe association between hyperuricemia and urolithiasis has been previously reported. However, this association is based on observational data which are prone to residual confounding. The aim of this work was to evaluate if this relationship represents a causal effect of hyperuricemia, using Mendelian randomization.\n\n\nSTUDY DESIGN\nMendelian randomization (MR) analysis using two approaches: two-stage MR and two-sample MR.\n\n\nSETTING\n& participants: Participants aged 40-69 years from the UK Biobank Resource EXPOSURE: Serum urate OUTCOME: Urolithiasis ANALYTICAL APPROACH: An observational analysis testing for an association between serum urate and urolithiasis was performed using logistic regression. For MR analyses, serum urate-associated single nucleotide polymorphisms, identified from genome-wide association data, were used as instrumental variables for serum urate. In the two-stage MR analysis, a weighted genetic urate score was calculated from the instrumental variables, and a control function estimation model was fit. In the two-sample MR analysis, multiple-instrument MR via the inverse-variance weighted method was performed.\n\n\nRESULTS\nIndividual-level data were available for 359,827 participants of whom 6,398 (1.8%) reported urolithiasis. In the observational analysis, serum urate was positively associated with urolithiasis in an unadjusted analysis (OR [95% CI] 1.47 [1.42-1.51]); however, after adjustment for relevant confounders, no association was observed (OR [95% CI] 1.03 [0.99-1.08]). In the two-stage MR analysis, no significant causal effect of serum urate on urolithiasis was observed in the unadjusted (OR [95% CI] 0.93 [0.81-1.08]) or adjusted (OR [95% CI] 0.94 [0.80-1.09]) models. In the two-sample MR analysis, multiple-instrument MR did not indicate a causal effect of serum urate on urolithiasis.\n\n\nLIMITATIONS\nStone composition and urinalysis data, including urine pH, were not available for this study.\n\n\nCONCLUSIONS\nOur analyses do not support a causal effect of serum urate on urolithiasis. The association between serum urate and urolithiasis reported in observational studies is likely due to residual confounding. INDEX WORDS: urate, gout, kidney stones, urolithiasis, Mendelian randomization.