Hyperuricemia subtypes classified according to renal uric acid handling manifest distinct phenotypic and genetic profiles in people with gout

Objective Hyperuricemia can be stratified into four subtypes according to renal uric acid handling. The aim of this study was to comprehensively describe the biological characteristics (including genetic background) of clinically defined hyperuricemia subtypes in two large geographically independent gout cohorts. Methods Hyperuricemia subtype was defined as renal uric acid overload (ROL), renal underexcretion (RUE), combined, or renal normal. Twenty single nucleotide polymorphisms (SNP) previously identified as gout‐risk loci or associated with serum urate (SU) concentration in the East Asian population were genotyped. Weighted polygenic risk scores were calculated to assess the cumulative effect of genetic risks on the subtypes. Results Of the 4873 participants, 8.8% had ROL subtype, 60.9% RUE subtype, 23.1% combined subtype and 7.2% normal subtype. The ROL subtype independently associated with older age of onset, lower SU, tophi and diabetes; the RUE associated with lower BMI and non‐diabetes; the combined subtype associated with younger age of onset, higher BMI, SU and eGFR and smoking; and the normal subtype independently associated with older age of onset, lower SU and eGFR. Thirteen SNPs were associated with gout, with 6 shared loci and subtype‐dependent risk loci patterns. High polygenic risk scores associated with ROL subtype (OR=9.63, 95% CI 4.53‐15.12), RUE subtype (OR=2.18, 95% CI 1.57‐3.03) and the combined subtype (OR=6.32, 95% CI 4.22‐9.48) compared with low polygenic risk scores. Conclusion Hyperuricemia subtypes classified according to renal uric acid handling have subtype‐specific clinical and genetic features, suggesting subtype‐unique pathophysiological mechanisms.