Serum Urate and Kidney Function in Japanese Cohorts: Mendelian Randomization and Biomarker-Dependent Associations of...

Experimental studies have linked elevated serum urate (SUA) to kidney injury; however, Mendelian randomization (MR) studies and randomized trials have not consistently supported a causal effect on kidney outcomes. Japanese populations are enriched for the URAT1 loss-of-function variant rs121907892, allowing evaluation of a biologically specific question related to tubular urate transport. We examined the association of genetically predicted SUA with kidney function and, separately, the association of rs121907892 with kidney function measures in Japanese cohorts.

We performed a two-sample MR analysis using 34 genome-wide significant SUA-associated variants from BioBank Japan. Genetic associations with SUA were obtained from the Japan Multi-Institutional Collaborative Cohort Study (n=10,428), and associations with kidney function were obtained from the Tohoku Medical Megabank Organization cohort (n=47,066). Kidney function was assessed using creatinine- and cystatin C-based estimated glomerular filtration rate (eGFR). We also evaluated the association of rs121907892 with these measures.

Polygenic MR showed no evidence of an association between genetically predicted SUA and kidney function, with null findings for creatinine-based eGFR (inverse-variance weighted β=-0.031; 95% confidence interval [CI], -0.138 to 0.075; P=0.56) and cystatin C-based eGFR (β=-0.020; 95% CI, -0.123 to 0.084; P=0.71). In contrast, the rs121907892 A allele was associated with higher creatinine-based eGFR (β=0.047; 95% CI, 0.005 to 0.089; P=0.03), but not with cystatin C-based eGFR (β=-0.002; 95% CI, -0.044 to 0.040; P=0.97).

Polygenic MR provided no evidence that genetically predicted SUA has a major causal effect on kidney function in Japanese cohorts. The rs121907892 findings indicate a biomarker-dependent, variant-specific association.