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Objective: Hyperuricemia can be stratified into four subtypes according to renal uric acid handling. The aim of this study was to comprehensively describe the biologic 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 uric acid underexcretion (RUE), combined, or renal normal. Twenty single nucleotide polymorphisms (SNPs) 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 4,873 participants, 8.8% had an ROL subtype, 60.9% RUE subtype, 23.1% combined subtype, and 7.2% normal subtype. The ROL subtype was independently associated with older age at onset, lower SU, tophi, and diabetes mellitus; RUE was associated with lower body mass index (BMI) and non–diabetes mellitus; the combined subtype was associated with younger age at onset, higher BMI, SU, estimated glomerular filtration rate (eGFR), and smoking; and the normal subtype was independently associated with older age at 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 were associated with ROL subtype (odds ratio [OR] = 9.63, 95% confidence interval [95% CI] 4.53–15.12), RUE subtype (OR = 2.18, 95% CI 1.57–3.03), and 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 pathophysiologic mechanisms. [ABSTRACT FROM AUTHOR]

According to Hückel's rule, cyclic species are aromatic if they have 4n + 2 (n = 0, 1, 2, etc.) π electrons. However, large aromatic rings (atom number > 4) with minimum 2π electrons (i.e., n = 0) are rather rare because of the structural instability stemming from the deficient π electrons compared to the ring size. To date, the largest 2π-aromatic ring is a five-membered Ga5 core reported in a recent experiment. Herein, density functional theory calculations predicted seven inverse-sandwich Na2(MH)5 and half-sandwich Ca(MH)5 or Ca(MH)6 (M = Al, Ga or In) structures. They all have planar central five- or six-membered Al/Ga/In rings, rather negative binding energies and large HOMO–LUMO gaps. Their dianionic metal rings exhibit obvious aromatic characters and appreciable diatropic ring currents due to the good delocalization of 2π electrons donated by the Na/Ca metals. Interestingly, they also have novel collective bonding with the Na/Ca atoms interacting with both the metal ring and surrounding H atoms. These metalloaromatic rings not only greatly enrich the precious family of 2π aromatics, but also increase the maximum ring atom number from five to six, thus paving the way for Hückel-type 2π-aromatic large rings. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion Mechanisms underlying the adolescent‐onset and early‐onset gout are unclear. This study aimed to discover variants associated with early‐onset gout.We conducted whole‐genome sequencing in a discovery adolescent‐onset gout cohort of 905 individuals (gout onset 12 to 19 years) to discover common and low‐frequency single‐nucleotide variants (SNVs) associated with gout. Candidate common SNVs were genotyped in an early‐onset gout cohort of 2,834 individuals (gout onset ≤30 years old), and meta‐analysis was performed with the discovery and replication cohorts to identify loci associated with early‐onset gout. Transcriptome and epigenomic analyses, quantitative real‐time polymerase chain reaction and RNA sequencing in human peripheral blood leukocytes, and knock‐down experiments in human THP‐1 macrophage cells investigated the regulation and function of candidate gene RCOR1.In addition to ABCG2, a urate transporter previously linked to pediatric‐onset and early‐onset gout, we identified two novel loci (Pmeta < 5.0 × 10−8): rs12887440 (RCOR1) and rs35213808 (FSTL5‐MIR4454). Additionally, we found associations at ABCG2 and SLC22A12 that were driven by low‐frequency SNVs. SNVs in RCOR1 were linked to elevated blood leukocyte messenger RNA levels. THP‐1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation.This is the first comprehensive genetic characterization of adolescent‐onset gout. The identified risk loci of early‐onset gout mediate inflammatory responsiveness to crystals that could mediate gouty arthritis. This study will contribute to risk prediction and therapeutic interventions to prevent adolescent‐onset gout. [ABSTRACT FROM AUTHOR]

Access to clean and safe drinking water is essential. This study aimed to evaluate the effect of a kind of small molecular natural mineral water, C-cell mineral water on hyperuricemia male mice metabolism condition. A 13-week drinking water intervention study was conducted in Uox -knockout mice (KO). The hepatic metabolite profiling and related genes expression were detected by UPLC-TOF-MS and transcriptomic, and the gut microbiota of KO mice was determined by metagenomics sequencing. Results showed that the body weight of mice fed with C-cell water was remarkably lower than that of control mice on D 77 and D 91. Hepatic metabolite profiling revealed a shift in the pathway of glycine, serine and threonine metabolism, pantothenate and CoA biosynthesis, and biosynthesis of cofactors in KO mice fed with C-cell mineral water. Increased energy metabolism levels were related to increased hepatic expression of genes responsible for coenzyme metabolism and lipid metabolism. Gut microbiota was characterized by increasing activity of beneficial bacteria Blautia , and reducing activity of pathobiont bacteria Parasutterella . These genera have been reported to be associated with obesity. Small molecular mineral-rich natural water ingestion regulates metabolism and gut microbiota, protecting against obesity induced by hyperuricemia through mediating a microbiota-liver axis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Guo, He, Li, Sun, Yuan, Liu, Li, Merriman, Li and Zhang.)