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Mer tyrosine kinase (MerTK) has been found to regulate the secretion of inflammatory factors and exert immunosuppressive effects, but its role in gout remains unclear. In this study, we aimed to clarify the immnue effects of MerTK in gout. MerTK in synovium or serum of gout patients was determined by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and real-time quantitative polymerase chain reaction (RT-qPCR). In monosodium urate (MSU)-induced gout mice, the effect of MerTK inhibitor (UNC2250) on inflammation and polarization was also assessed. After inhibition, knockdown or overexpression of MerTK, inflammatory response and polarization level in THP1-derived macrophages were evaluated by RT-qPCR and flow cytometry. Regulation of MerTK inhibitors on mitochondrial function and downstream pathway in THP1-derived macrophages were detected. MerTK in synovium and serum of gout patients were increased. MerTK inhibitor stimulated the inflammation and M1 polarization in MSU-induced gout mice. MerTK inhibition, knock-down, or overexpression affected inflammatory response, polarization and mitochondrial function in vitro in gout model. The PI3K/Akt/GSK-3β pathway was identified to reduce after MerTK inhibition and the relevant results were as expected, validated by knock-down or overexpressing MerTK. In conclusion, MerTK was detected to increase in both gout patients and model. MerTK influenced inflammatory response and polarization markers through PI3K/Akt/GSK-3β pathway. Interfering MerTK/PI3K/Akt/GSK-3β axis may provide a new therapeutic target for gout., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The causal relationship between visceral adipose tissue (VAT) and gout is still unclear. We aimed to examine the potential association between them using observational and Mendelian randomization (MR) analyses., Methods: In the observational analyses, a total of 11,967 participants (aged 39.5 ± 11.5 years) were included from the National Health and Nutrition Examination Survey. Logistic regression models were used to investigate the association between VAT mass and the risk of gout. In two-sample MR analyses, 211 VAT mass-related independent genetic variants (derived from genome-wide association studies in 325,153 UK biobank participants) were used as instrumental variables. The random-effects inverse-variance weighted (IVW) method was used as the primary analysis. Additional sensitivity analyses were also performed to validate our results., Results: Observational analyses found that an increase in VAT mass (per standard deviation) was associated with a higher risk of gout after controlling for confounding factors (odds ratio [OR] = 1.27, 95% confidence intervals [CI] = 1.11-1.45). The two-sample MR analyses demonstrated a causal relationship between increased VAT mass and the risk of gout in primary analyses (OR = 1.78, 95% CI = 1.57-2.03). Sensitivity analyses also showed similar findings, including MR-Egger, weighted median, simple mode, weighted mode, and leave-one-out analyses., Conclusions: Observational analyses showed a robust association of VAT mass with the risk of gout. Meanwhile, MR analyses also provided evidence of a causal relationship between them. In summary, our findings suggested that targeted interventions for VAT mass may be beneficial to prevent gout., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Objective: Spontaneous serum uric acid (SUA) decrease has been found in many patients during acute gout attacks, but its mechanism remains unclear., Methods: The spontaneous regulation of SUA during a gout attack and its possible causes were evaluated in patients with gout. The mechanism of the spontaneous SUA decrease was further studied in Caco2 cells and a monosodium urate (MSU)-induced gout model of wild-type mice and ABCG2-/- mice. The urate transport function of intestinal epithelial cells was detected by transwell culture of Caco2 cells. Expression of ATP-binding cassette super-family G member 2 (ABCG2), IL-1β and phosphoinositide 3-kinase (PI3K)/Akt was analysed using real-time PCR, western blotting, or immunofluorescence assays., Results: SUA decreased during acute gout attacks in both the gout patients and MSU-induced gouty mice. Increased serum CRP and IL-1β levels were correlated with the SUA decrease. Intestinal uric acid excretion and expression of ABCG2 were upregulated in the mice during acute gout attacks. In the ABCG2-/- mice, intestinal uric acid excretion significantly decreased during gout attacks. In an in vitro study of a transwell culture, ABCG2 and its upstream PI3K/Akt pathway were significantly upregulated in intestinal epithelial cells. However, ABCG2 expression and its associated intestinal uric acid transport were inhibited when PI3K/Akt was blocked by a PI3K inhibitor, LY294002., Conclusions: Increased intestinal urate excretion resulted in spontaneous SUA downregulation during acute gout attacks. Inflammation-induced PI3K/Akt activation and ABCG2 expression in epithelial cells might contribute to the upregulation of intestinal uric acid excretion., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Macrophage polarization mediates the development of inflammatory diseases. However, the polarization status at various stages of gout is not fully understood. Our study aimed to define the evolution of macrophage polarization in acute and chronic gout. Normal human synovium and synovium with tophi were collected for immunofluorescence (IF). Rat gouty joints were collected for joint thickness assessment and pathological evaluation. Tissue mRNA expression of inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) were evaluated. Mouse peritoneal macrophages and THP-1 derived macrophages were stimulated by monosodium urate (MSU) crystals and were collected for detection of interleukin (IL) -1β and IL-37 levels and iNOS/Arg-1 ratio. Arg-1 and IL-37 were highly expressed in normal synovium and synovium with tophi. In rat gouty joints, the inflammatory cell counts and ankle thickness began to increase at 2 h, peaked at 24 h, and was decreased spontaneously. An increase in macrophages preceded the neutrophils infiltration. Infiltration of M1 was positively related with the severity of arthritis. M2 appeared in an early stage (at 2 h) of inflammation. The number of M1 macrophages was comparable to that of M2 from 2 to 12 h and exceeded M2 number at 18 h and 24 h. The ratios of M2/M1 reversed at 48 h and remained reversed until 120 h. In mice gouty joints, iNOS/Arg-1 mRNA ratio was significantly higher than the that in control group at 8 h. The proportion of neutrophils and M1-macrophages reached peak at 4 h in mice model with peritoneal gout. Concentration of IL-1β and ratio of iNOS/Arg-1 were increased at 6 h, peaked at 48 h, and were then decreased at 72 h in vitro, while the concentration of IL-37 peaked at 2 h and then decreased. In summary, altered macrophage polarization was observed in various stages of gouty inflammation. Macrophages in acute gout were polarized into M1 at early stage and into M2 at later stage while the macrophages in chronic gout mainly were only polarized towards M2. The number of M1 rose with the progression of inflammation. Early increase of M2 was observed, which might be generated directly from M0., (© 2022. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

Objective: Interleukin (IL)-37 is a natural suppressor of inflammation. Macrophages play an important role in acute gout flare by dominating the inflammation and spontaneous relief. We have reported that IL-37 could limit runaway inflammation in gout. Here we focus on whether IL-37 inhibits gouty inflammation by altering macrophage functions, and how it does so., Methods: Macrophage functions were evaluated in terms of phagocytosis, pyroptosis, polarization and metabolism. Phagocytosis and polarization of macrophages were detected by side scattering and double-labelling induced nitrogen monoxide synthase (iNOS)/arginase-1 (Arg-1) using flow cytometry, respectively. Transcription of pyroptosis-related molecules was detected by qPCR. Metabolomics was performed by liquid chromatograph mass spectrometer. Human IL-37 knock-in mice and a model with point mutation (S9A) at mouse Gsk3b locus were created by CRISPR/Cas-mediated genome engineering. MSU was injected into the paws and peritoneal cavity to model acute gout. Vernier calliper was used to measure the thickness of the paws. The mice paws and human synovium tissues or tophi were collected for pathological staining. Peritoneal fluid of mice was used to enrich macrophages to detect polarization., Results: IL-37 promoted non-inflammatory phagocytic activity of macrophages by enhancing phagocytosis of MSU, reducing transcription of pyroptosis-related proteins and release of inflammatory cytokines, protecting mitochondrial function, and mediating metabolic reprogramming in MSU-treated THP-1 cells. These multifaceted roles of IL-37 were partly depended on the mediation of glycogen synthase kinase-3β (GSK-3β)., Conclusions: Our study revealed that IL-37 could shape macrophages into a 'silent' non-inflammatory phagocytic fashion. IL-37 may become a potentially valuable treatment option for patients of chronic gout, especially for those with tophi., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Gout is a common arthritis caused by deposition of monosodium urate crystals. Macrophage is crucial in the process of monosodium urate (MSU)-induced inflammation. Although it has been reported that adrenocorticotropic hormone (ACTH) in nature can be used to cure urarthritis, the mechanism concerning macrophage is still not clear. However, gout patients manifest other complications, such as hypertension, diabetes, chronic kidney disease, and hormone intolerance, which limit efficacy of some of these first-line drugs. Therefore, this study aims to explore how natural ACTH can alleviate urarthritis through functional changes in macrophage. We analyzed the variations in VAS pain scores of five patients, knowing the time of action and detecting the level of cortisol and ACTH in patients 24 hours after the application of ACTH. The effect of natural ACTH on joint inflammation and the level of cortisol in blood in the mouse model was evaluated by studies in vivo. In vitro studies, we evaluated the effect of natural ACTH on macrophages and revealed different functions of ACTH and dexamethasone on macrophages in the transcriptional level. In patients with acute gout, natural ACTH can quickly alleviate pain and does not affect the level of cortisol and ACTH. Natural ACTH is able to ease the swelling and inflammatory cell infiltration caused by arthritis, without changing the level of cortisol. Besides, natural ACTH in vitro can alleviate acute gouty inflammation by regulating phagocytosis and polarization of macrophage, which also exerts different effects on the transcription of some related genes. Natural ACTH is able to alleviate acute gouty inflammation by regulating macrophage, and this effect differs from that of dexamethasone at the transcriptional level., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Rui Xu et al.)

Background: Si-Miao-San (SMS) is a well-known traditional Chinese medicine. This study aims to evaluate the anti-inflammatory effects of SMS on gouty arthritis and its potential mechanism of action., Methods: The effects and mechanism of SMS were evaluated in monosodium urate (MSU)-treated mice or macrophages. The expression of cytokines and PI3K/Akt was analyzed using real-time PCR and Western blotting analyses. Macrophage polarization was assessed with immunofluorescence assays, real-time PCR, and Western blotting. Mass spectrometry was used to screen the active ingredients of SMS., Results: Pretreatment with SMS ameliorated MSU-induced acute gouty arthritis in mice with increased PI3K/Akt activation and M2 macrophage polarization in the joint tissues. In vitro , SMS treatment significantly inhibited MSU-triggered inflammatory response, increased p-Akt and Arg-1 expression in macrophages, and promoted M2 macrophage polarization. These effects of SMS were inhibited when PI3K/Akt activation was blocked by LY294002 in the macrophages. Moreover, SMS significantly reduced serum uric acid levels in the hyperuricemia mice. Using mass spectrometry, the plant hormones ecdysone and estrone were detected as the potentially effective ingredients of SMS., Conclusion: SMS ameliorated MSU-induced gouty arthritis and inhibited hyperuricemia. The anti-inflammatory mechanism of SMS may exert anti-inflammatory effects by promoting M2 polarization via PI3K/Akt signaling. Ecdysone and estrone might be the potentially effective ingredients of SMS. This research may provide evidence for the application of SMS in the treatment of gout., 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 © 2022 Cao, Zhao, Xue, Xue, Chen, Quan, Xiao, Wan, Han, Jiang, Lu, Zou and Zhu.)

Objective: To evaluate monosodium urate (MSU) crystal deposition and related lesions in the joints of patients with gout and hyperuricemia (HUA) using ultrasound. To explore the association between ultrasound findings and clinical features in gout and HUA., Methods: A total of 202 patients with gout and 43 asymptomatic patients with HUA were included. The clinical data and ultrasonic assessment results were collected and statistically analyzed., Results: Deposition of MSU crystals was found in 25.58% (11/43) of patients with asymptomatic HUA and 76.24% (154/202) of patients with gout. Of the 1,082 joints from patients with gout examined, 33.09% (358/1082) displayed MSU crystal deposition. In the joints with MSU crystal deposition, 77.37% (277/358) had a history of attacks. Among the joints of gouty arthritis, double contour sign (DCS), hyperechoic aggregate (HAG), and tophi were found in 32.65% (159/487), 7.80% (38/487), and 24.64% (120/487) of the joints, respectively. DCS and tophi, but not HAG, increasingly appeared with the extension of gout duration. In patients with more than 15 years of gout history, DCS, Tophi, and HAG were found in 48.18%, 40.00%, and 6.36% of US assessed joints, respectively. In patients with gout, synovial lesion and bone erosion were found in 17.74% (192/1082) and 7.58% (82/1082) of joints, respectively. The synovial lesion was related to HAG, while bone erosion was related to tophi and DCS. Nephrolithiasis was detected in 20.30% (41/202) of patients with gout and 4.65% (2/43) of HUA patients, indicating that nephrolithiasis occurred in more patients with gout than in patients with HUA., Conclusion: HAG is an early performance of MSU crystal deposition in joints of gout and HUA. Both DCS and tophi are risk factors for bone erosion. Early urate-lowering therapy (ULT) should be considered in patients with gout, DCS, or tophi., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Ling Cao et al.)

Background: Genetic background affects serum urate concentration and gout risk, especially regarding these variants in the urate-transporter gene ABCG2. However, the role of epistasis between PKD2 and ABCG2 on the pathogenesis of gout is poorly understood. Here we assess this epistatic interaction in the progression from elevated serum urate to gout., Results: We identified two epistatic interaction pairs (rs2728121: rs1481012 and rs2728121: rs2231137) were associated with urate levels in 4914 Chinese individuals (P int  = 0.018 and 0.004, respectively). Using subgroup analysis for gender and BMI, we found the degree of associations was varied by gender and BMI. The SNP pair rs2728121:rs1481012 influenced urate levels in females and overweight subjects (P int  = 0.006 and 0.022, respectively), but rs2728121:rs2231137 did in males, overweight and normal-weight subjects (P int  = 0.017, 0.047 and 0.013, respectively). Consistent results were also observed in associations between these epistatic interactions with hyperuricemia. Next, the SNP pair rs2728121:rs2231137 was identified to influence the development of gout from both hyperuricemia and healthy (P int  = 0.035 and 0.001, respectively), especially in males (P int  = 0.030 and 0.001, respectively). Furthermore, we demonstrated that interacting regions were enriched by regulatory elements. Finally, we observed a strong gene co-expression pattern between PKD2 and ABCG2 (r = 0.743, P = 5.83E-06)., Conclusion: Our findings indicate epistasis between PKD2 and ABCG2 influence serum urate concentrations, hyperuricemia and gout risk, thus providing insight into the pathogenesis of gout.

Aims: To evaluate the fluctuation of serum uric acid (SUA) during acute gout (AG) and explore its potential mechanisms., Methods: Data such as SUA, urinary uric acid and 24-hour uric acid urinary excretion were collected from 126 patients diagnosed with gout and were analyzed., Results: Serum uric acid was negatively correlated with age in gout patients, and significantly elevated in patients aged ≤50 years. Twenty-four-hour uric acid urinary excretion was affected by SUA, creatinine clearance, age, body mass index and urine volume. In contrast, clearance of uric acid and fractional excretion of uric acid (FEur) were more stable. SUA was significantly downregulated during acute attacks. Of the AG patients, 34.92% had detected SUA <420 μmol/L. Clearance of uric acid and FEur were notably increased in patients during acute attacks, especially in patients with SUA <420 μmol/L., Conclusion: This study demonstrated that the level of SUA was remarkably upregulated in young gout patients. Therefore, early onset of gout should be considered of great importance. SUA was downregulated during acute gouty arthritis, which might be associated with increased urinary excretion of uric acid., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

The aims of this study were to identify candidate pathways associated with serum urate and to explore the genetic effect of those pathways on the risk of gout. Pathway analysis of the loci identified in genome-wide association studies (GWASs) showed that the ion transmembrane transporter activity pathway (GO: 0015075) and the secondary active transmembrane transporter activity pathway (GO: 0015291) were both associated with serum urate concentrations, with P FDR values of 0.004 and 0.007, respectively. In a Chinese population of 4,332 individuals, the two pathways were also found to be associated with serum urate (P FDR  = 1.88E-05 and 3.44E-04, separately). In addition, these two pathways were further associated with the pathogenesis of gout (P FDR  = 1.08E-08 and 2.66E-03, respectively) in the Chinese population and a novel gout-associated gene, SLC17A2, was identified (OR = 0.83, P FDR  = 0.017). The mRNA expression of candidate genes also showed significant differences among different groups at pathway level. The present study identified two transmembrane transporter activity pathways (GO: 0015075 and GO: 0015291) were associations with serum urate concentrations and the risk of gout. SLC17A2 was identified as a novel gene that influenced the risk of gout.

Background: Genome-wide association studies (GWASs) have identified dozens of loci associated with gout, but for most cases, the risk genes and the underlying molecular mechanisms contributing to these associations are unknown. This study sought to understand the molecular mechanism of a common genetic variant, rs780093, in the development of gout, both in vitro and in vivo., Results: Nuclear receptor binding protein 1 ( NRBP1 ), as a gout risk gene, and its regulatory region, 72 bp upstream of the transcription start site, designated as B1, were identified through integrative analyses of genome-wide genotype and DNA methylation data. We observed elevated NRBP1 expression in human peripheral blood mononuclear cells (PBMCs) from gout patients. In vitro luciferase reporter and protein pulldown assay results showed that DNA methylation could increase the binding of the transcription factor TFAP2A to B1, leading to suppressed gene expression. There results were further confirmed by in vivo bisulfite pyrosequencing showing that hypomethylation on B1 is associated with increased NRBP1 expression in gout patients., Conclusions: Hypomethylation at the promoter region of NRBP1 reduces the binding of TFAP2A and thus leads to elevated NRBP1 expression, which might contribute to the development of gout.

Gout is a common arthritis resulting from increased serum urate, and many loci have been identified that are associated with serum urate and gout. However, their influence on the progression from elevated serum urate levels to gout is unclear. This study aims to explore systematically the effects of genetic variants on the pathogenesis in approximately 5,000 Chinese individuals. Six genes (PDZK1, GCKR, TRIM46, HNF4G, SLC17A1, LRRC16A) were determined to be associated with serum urate (P FDR  < 0.05) in the Chinese population for the first time. ABCG2 and a novel gene, SLC17A4, contributed to the development of gout from hyperuricemia (OR = 1.56, P FDR  = 3.68E-09; OR = 1.27, P FDR  = 0.013, respectively). Also, HNF4G is a novel gene associated with susceptibility to gout (OR = 1.28, P FDR  = 1.08E-03). In addition, A1CF and TRIM46 were identified as associated with gout in the Chinese population for the first time (P FDR  < 0.05). The present study systematically determined genetic effects on the progression from elevated serum urate to gout and suggests that urate-associated genes functioning as urate transporters may play a specific role in the pathogenesis of gout. Furthermore, two novel gout-associated genes (HNF4G and SLC17A4) were identified.

Background: Interleukin (IL)-37 has emerged as a fundamental inhibitor of innate immunity. Acute gout is a self-limiting inflammatory response to monosodium urate (MSU) crystals. In the current study, we assessed the preventive and therapeutic effect of recombinant human IL-37 (rhIL-37) in human and murine gout models., Methods: We investigated the expression of IL-37 in patients with active and inactive gouty arthritis and assessed the effect of rhIL-37 in human and murine gout models: a human monocyte cell line (THP-1) and human synovial cells (containing macrophage-like and fibroblast-like synoviocytes) exposed to MSU crystals, a peritoneal murine model of gout and a murine gouty arthritis model. After inhibition of Mer receptor tyrosine kinase (Mertk), levels of IL-1β, IL-8 and chemokine (C-C motif) ligand 2 (CCL-2) were detected by ELISA and expression of mammalian homologs of the drosophila Mad gene 3 (Smad), suppressor of cytokine signaling 3 (SOCS3), NACHT-LRR-PYD-containing protein 3 (NLRP3), and IL-8R of THP-1 were assessed by qPCR and western blot to explore the molecular mechanisms., Results: Our studies strongly indicated that rhIL-37 played a potent immunosuppressive role in the pathogenesis of experimental gout models both in vitro and in vivo, by downregulating proinflammatory cytokines and chemokines, markedly reducing neutrophil and monocyte recruitment, and mitigating pathological joint inflammation. In our studies, rhIL-37 suppressed MSU-induced innate immune responses by enhancing expression of Smad3 and IL-1R8 to trigger multiple intracellular switches to block inflammation, including inhibition of NLRP3 and activation of SOCS3. Mertk signaling participated in rhIL-37 inhibitory pathways in gout models. By inhibition of Mertk, the anti-inflammatory effect of rhIL-37 was partly abrogated, and IL-1R8, Smad3 and S​OCS3 expression were suppressed, whereas NLRP3 expression was reactivated., Conclusions: Our studies reveal that IL-37 limits runaway inflammation initiated by MSU crystal-induced immune responses, partly in a Mertk-dependent fashion. Thus, rhIL-37 has both preventive and therapeutic effects in gouty arthritis.

Gout is a common inflammation disease resulting from an increase in serum uric acid. Nearly 70% of uric acid is excreted via the kidneys. To date, evidence for an association between genetic loci and gout is absent, equivocal or not replicated. Our study aims to test variants in two genes abundantly expressed in the kidney, LRP2 and COMT, for their association with uric acid and gout. In total, 1318 Chinese individuals were genotyped for rs2544390 in LRP2 and rs4680 in COMT. These LRP2 and COMT gene polymorphisms showed no significant effect on uric acid (P = 0.204 and 0.188, separately); however, rs2544390 in LRP2 did influence uric acid levels in individuals with BMI ≥ 25 (P = 0.009). In addition, the allele frequency distributions of the two loci showed a significant difference between gout patients and healthy controls. A missense variation in rs4680 (G > A) decreased the risk of gout (OR = 0.77, P = 0.015), whereas the T allele of rs2544390 was associated with gout pathogenesis risk (OR = 1.26, P = 0.020). The present study provides the first evidence for an association between COMT and gout. Rs2544390 in LRP2 only influenced uric acid levels in individuals with BMI ≥ 25, which might explain the discrepant results among previous studies. In addition, we are the first to identify the association between LRP2 and gout in a Chinese population and to confirm this association in Asians.

Gout is one of the most common types of inflammatory arthritis, caused by the deposition of monosodium urate crystals in and around the joints. Previous genome-wide association studies (GWASs) have identified many genetic loci associated with raised serum urate concentrations. However, hyperuricemia alone is not sufficient for the development of gout arthritis. Here we conduct a multistage GWAS in Han Chinese using 4,275 male gout patients and 6,272 normal male controls (1,255 cases and 1,848 controls were genome-wide genotyped), with an additional 1,644 hyperuricemic controls. We discover three new risk loci, 17q23.2 (rs11653176, P=1.36 × 10(-13), BCAS3), 9p24.2 (rs12236871, P=1.48 × 10(-10), RFX3) and 11p15.5 (rs179785, P=1.28 × 10(-8), KCNQ1), which contain inflammatory candidate genes. Our results suggest that these loci are most likely related to the progression from hyperuricemia to inflammatory gout, which will provide new insights into the pathogenesis of gout arthritis.

Aim: Original studies have employed various genetic models in association analysis between ABCG2 Q141K (rs2231142) with gout risk and different or conflicting results, especially regarding the role of gender in this association. In addition, it is not clear whether the association varies by ethnicity., Method: Articles published before September 1, 2013 were extracted and registered into databases for the systematic review of this polymorphism. The quality of each study was scored based on predefined criteria. The genetic model was identified through stratification analysis, then a meta-analysis including all publically available data was preformed to test the association between rs2231142 and gout risk. Potential sources of heterogeneity were sought out via stratification analysis and meta-regression analysis., Results: Nine case-control studies involving 17 942 individuals were eligible for the meta-analysis of rs2231142. Codominant model was the most appropriate genetic model to interpret the susceptibility cause. It showed that the rs2231142 T allele obviously increased gout risk, and TT was much stronger than GT (TT vs. GG: OR, 4.10; 95% CI, 2.90-5.80; GT vs. GG: OR, 1.71, 95% CI, 1.39-2.10). In addition, gender and ethnicity were found to affect the association between the susceptibility of gout and rs2231142., Conclusion: ABCG2 rs2231142 is an important genetic factor in increasing gout risk, and the difference in genetic association has been found between male and female populations. In addition, the degree of association has been found to vary with ethnicity., (© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Background: Gout is a common type of arthritis that is characterized by hyperuricemia, tophi and joint inflammation. Genetic variations in the ABCG2 gene have been reported to influence serum uric acid levels and to participate in the pathogenesis of gout, but no further data have been reported in the Han Chinese population., Methods: Peripheral blood DNA was isolated from 352 male patients with gout and 350 gout-free normal male controls. High-resolution melting analysis and Sanger sequencing were performed to identify the genetic polymorphisms V12M, Q141K and Q126X in the ABCG2 gene. Genotype and haplotype analyses were utilized to determine the disease odds ratios (ORs). A prediction model for gout risk using ABCG2 protein function was established based on the genotype combination of Q126X and Q141K., Results: For Q141K, the A allele frequency was 49.6% in the gout patients and 30.9% in the controls (OR 2.20, 95% confidence interval (CI): 1.77-2.74, p=8.99×10⁻¹³). Regarding Q126X, the T allele frequency was 4.7% in the gout patients and 1.7% in the controls (OR 2.91, 95% CI: 1.49-5.68, p=1.57×10⁻³). The A allele frequency for V12M was lower (18.3%) in the gout patients than in the controls (29%) (OR 0.55, 95% CI 0.43-0.71, p=2.55×10⁻⁶). In the order of V12M, Q126X and Q141K, the GCA and GTC haplotypes indicated increased disease risk (OR=2.30 and 2.71, respectively). Patients with mild to severe ABCG2 dysfunction accounted for 78.4% of gout cases., Conclusion: The ABCG2 126X and 141K alleles are associated with an increased risk of gout, whereas 12M has a protective effect on gout susceptibility in the Han Chinese population. ABCG2 dysfunction can be used to evaluate gout risk.

Objective: To determine the nationwide prevalence of hyperuricemia in China and evaluate its trends and associated risk factors. Methods: Using a multi-stage, stratified, cluster-randomized sampling design, two cross-sectional surveys (representative of national and provincial information) were conducted in 31 provinces (autonomous regions and municipalities) in mainland China, with 166, 861 Chinese adults in 2015–16 and 168, 351 in 2018–19. Serum uric acid (SUA) levels of all participants were measured after a >10-hour overnight fast. Hyperuricemia (HUA) was defined when SUA was >420 μmol/L. Prevalence estimates were weighted to represent the total population considering the complex sampling design. Multivariable logistic regression models was used to estimate factors associated with HUA. Results: The overall hyperuricemia prevalence in the Chinese adult population was 11.1% (95% confidence interval 10.3% to 11.8%) in 2015–16 and 14.0% (13.1% to 14.8%) in 2018–19; an alarming rise was observed in the three years. Hyperuricemia was more common in men with 19.3% (17.9% to 20.7%) in 2015–16 and 24.4% (23.0% to 25.8%) in 2018–19, although the prevalence also escalated from 2.8% (2.5% to 3.0%) in 2015–16 to 3.6% (3.2% to 4.0%) in 2018–19 in women. The hyperuricemia risk factors include the urban culture, settlement in the East, Zhuang descent, high education, heavy or frequent beer drinking, high red meat intake, physical inactivity, high body mass index, central obesity, hypertension, hyperlipidemia, and low glomerular filtration rate. Conclusion: The estimated hyperuricemia prevalence among Chinese adults was 14.0% in 2018-19; significant escalating trends were observed between 2015-16 and 2018-19. [ABSTRACT FROM AUTHOR]

Objectives Acute gout is an inflammatory response to MSU crystals. In our previous research, Sirt1 was shown to have an effect in preventing acute gouty inflammation. In the current study, we aimed to investigate the underlying mechanism involving Sirt1 in acute gout. Methods The cytological changes and Sirt1 expression in the synovium were observed in patients with acute or intermittent gout. The effect of Sirt1 and its mechanism in gout were studied in macrophages, C57BL/6 mice and Sirt1 +/− mice. Results Sirt1 expression was increased in the peripheral blood mononuclear cells (PBMCs) of patients with acute gout but not in the chronic tophus tissue. The arthritis score and numbers of inflammatory cells in injured paw tissue from murine gout models were upregulated in Sirt1 +/− mice compared with wild-type mice. A PCR array of the paw tissue from murine gout models indicated that Sirt1 activation might attenuate MSU-induced inflammation by altering the polarization state of macrophages. Furthermore, in patients with acute gout, the phagocytosis of MSU crystals by a macrophage was found in a smear of the joint fluid and large amounts of macrophages were also found in the synovium. The activation of Sirt1 in gouty mice actually decreased the tendency toward M1 polarization. The inhibition of PI3K/Akt partially blocked the anti-inflammatory effect of Sirt1 and the translocation of STAT6, and phosphorylated STAT6 expression was decreased in RAW 264.7 cells treated with MSU crystals. Conclusion Our studies revealed that Sirt1 ameliorates MSU-induced inflammation by altering macrophage polarization via the PI3K/Akt/STAT6 pathway. [ABSTRACT FROM AUTHOR]

Objectives To investigate features of urate deposition in gout and the association between these features and attacks of gouty arthritis using dual-energy computed tomography ( CT). Methods Dual-energy CT scans of both feet were performed in 80 consecutive patients with gout and 22 with asymptomatic hyperuricemia. Results Overall, 333 areas of urate deposition were found in patients with gout. The most commonly affected sites were the first metatarsophalangeal joint ( MPJ; 57/333), the distal area of the first toe (59/333) and the calcaneal bone (61/333). For episodes of the first MPJ arthritis, urate deposits in the flexor pollicis longus muscle tendon ( P = 0.02), as well as solitary and punctate depositions ( P = 0.03 and 0.01, respectively) were positively related to the acute attacks. For episodes of arthritis around the ankle, deposits in the area, including the talus and inferior tibia, were associated with attacks of arthritis at the ankle ( P = 0.02); additionally, deposits in the flexor tendon adjacent to the inferior tibia ( P < 0.01) and a punctiform conformation were significantly associated with attacks of arthritis ( P = 0.02). Logistic regression analysis showed that deposits around the first MPJ ( OR = 3.38, 95% CI: 1.32, 8.17) or around the talus and inferior tibia ( OR = 2.83, 95% CI: 1.11, 7.15) would increase the risk of an attack of arthritis. Conclusions Dual-energy CT imaging can be used to detect and analyze the features of urate deposition in patients with gout. Specific features of the deposits appeared to be associated with acute attacks of gouty arthritis. [ABSTRACT FROM AUTHOR]