Background/Purpose: For most people with gout, reduced renal clearance of uric acid is a key contributor to hyperuricemia.  It is increasingly recognized that gout has a genetic basis, and that renal clearance of uric acid is also genetically determined.  However, the factors that contribute most to reduced renal clearance of uric acid are unknown.  The aim of this study was to examine clinical and genetic factors associated with fractional excretion of uric acid (FEUA), including in the New Zealand Maori and Pacific population which has high prevalence of hyperuricemia and gout. 

Methods: New Zealand Maori, Pacific and European participants in the Genetics of Gout in Aotearoa study with available genotyping and FEUA data were included in this analysis (n=1713, 896 with gout and 817 without gout).  All participants completed a study visit which included clinical assessment and collection of blood and urine for urate and creatinine testing.  FEUA was calculated as the urate clearance/creatinine clearance, expressed as a percentage.  Participants with chronic kidney disease stage 5 were excluded from the analysis.  Associations with FEUA were tested using linear regression models. The top 10 loci previously associated with FEUA in a European population by GWAS (Kottgen, Nature Genetics 2013) were analysed.  For genetic analysis, P for experiment-wide significance was 0.005.

Results:  The mean (SD) FEUA in the entire study group was 5.5 (2.7)%.  Maori or Pacific participants had lower FEUA compared to European participants (mean (SD) FEUA 5.0 (2.6)% vs. 5.9 (2.7)%, P for difference=2×10-12).  The number of SLC2A9 rs11942223 risk alleles was associated with FEUA in European participants (age and sex-adjusted P=3 x 10-8).  Most (89%) Maori or Pacific participants had two SLC2A9 rs11942223 risk alleles, and no association between SLC2A9 and FEUA was observed in Maori or Pacific participants (age and sex-adjusted P=0.15).  No other tested loci met experiment-wide significance for association with FEUA.  In European participants, gout status, diuretic use, male sex, body mass index, and number of SLC2A9 risk alleles were independently associated with FEUA, and these five variables accounted for 37% of the variance of FEUA in the regression model (Table).  In contrast, in Maori or Pacific participants, these variables contributed to 19% of the variance of FEUA in the regression models (Table).

Conclusion : Both genetic and non-genetic factors contribute to renal clearance of uric acid.  SLC2A9 exerts population-specific effects on FEUA, with effects observed in European, but not Maori or Pacific people.