Upregulated expression of FFAR2 and SOC3 genes is associated with gout.

OBJECTIVE: To examine the expression of Free fatty acid receptor 2 (FFAR2) and Suppressor of cytokine signalling 3 (SOCS3) genes in asymptomatic hyperuricaemia (AH), AH with MSU crystal deposition, inter-critical gout and gout flare. METHODS: Study participants (n = 120) comprised 34 people with serum urate (SU) <360 µmol/l, 69 with AH ± MSU crystal deposition and 17 with a gout flare. Sixteen of the 17 patients with a gout flare attended a second visit 6-12 weeks later. Gene expression levels were assessed using RT-qPCR and results computed as fold changes (FC) after normalization to the reference gene. RESULTS: FFAR2 was significantly upregulated during gout flares (FC = 2.9) compared with normal SU, AH, and AH + MSU crystal deposition (FC = 1.1, P < 0.0001 for each comparison). FFAR2 was also significantly upregulated during inter-critical gout (FC = 1.8) compared with normal SU, AH and AH + MSU (FC = 1.1, P < 0.001 for each comparison). SOCS3 was significantly upregulated during gout flares (FC = 3.4) compared with normal SU, AH, and AH + MSU crystal deposition (FC = 1.1, 1.1 and 1.2, respectively, P < 0.0001 for each comparison). SOCS3 was also upregulated during inter-critical gout (FC = 2.1) compared with normal SU (P = 0.02) and AH (P = 0.006) (FC = 1.1 and 1.2, respectively). FFAR2 expression was upregulated during gout flare compared with inter-critical gout and SOCS3 expression showed negative correlation with flare duration (r = -0.49, P < 0.05). CONCLUSION: FFAR2 upregulation is associated with gout and may trigger gout flares. SOCS3 may have a role in amelioration of gout flares.

Are polymorphisms affecting serum urate, renal urate handling and alcohol intake associated with co-morbidities in gout cases? A case-control study using data from the UK Biobank.

To examine the association between common comorbidities, eGFR and loci involved in the hyperuricaemia-gout transition. This study was conducted in people with gout from the UK Biobank. Logistic regression was used to examine the association between self-reported physician-diagnosed hypertension, diabetes, hypercholesterolemia and ischaemic heart disease (IHD) with the following variants: rs1260326(GCKR), rs16890979(SLC2A9), rs2231142(ABCG2), rs1229984(ADH1B) and rs2078267(SLC22A11) and adjusted for age, sex and 10-principal components. Linear regression was used to examine the association with eGFR. 7,049 participants with gout were included. After adjusting for multiple testing, there was a statistically significant positive association between urate lowering allele at SLC2A9 and hypertension, and negative association between urate raising allele at ABCG2 and hypertension (OR 1.17 and OR 0.86, respectively). Number of urate lowering risk alleles associated with hypertension [OR (95%CI) 1.13 (1.06-1.21)]. High eGFR associated with urate raising allele at rs2231142 (ß = 1.38). The SNP in ADH1B that protects from alcohol excess showed a negative association with IHD (OR 0.53). Unlike in general population studies urate lowering genetic variants associate with hypertension in gout patients with dose-response. This may be due to high prevalence of other risk factors of hypertension such as obesity, poor diet etc. and needs validation in independent datasets.

Variants in urate transporters, ADH1B, GCKR and MEPE genes associate with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank.

OBJECTIVES: To perform a genome-wide association study (GWAS) of gout cases versus asymptomatic hyperuricaemia (AH) controls, and gout cases versus normouricaemia controls, and to generate a polygenic risk score (PRS) to determine gout-case versus AH-control status. METHODS: Gout cases and AH controls (serum urate (SU) ≥6.0 mg/dL) from the UK Biobank were divided into discovery (4934 cases, 56 948 controls) and replication (2115 cases, 24 406 controls) cohorts. GWAS was conducted and PRS generated using summary statistics in discovery cohort as the base dataset and the replication cohort as the target dataset. The predictive ability of the model was evaluated. GWAS were performed to identify variants associated with gout compared with normouricaemic controls using SU <6.0 mg/dL and <7.0 mg/dL thresholds, respectively. RESULTS: Thirteen independent single nucleotide polymorphisms (SNPs) in ABCG2, SLC2A9, SLC22A11, GCKR, MEPE, PPM1K-DT, LOC105377323 and ADH1B reached genome-wide significance and replicated as predictors of AH to gout transition. Twelve of 13 associations were novel for this transition, and rs1229984 (ADH1B) was identified as GWAS locus for gout for the first time. The best PRS model was generated from association data of 17 SNPs; and had predictive ability of 58.5% that increased to 69.2% on including demographic factors. Two novel SNPs rs760077(MTX1) and rs3800307(PRSS16) achieved GWAS significance for association with gout compared with normouricaemic controls using both SU thresholds. CONCLUSION: The association of urate transporters with gout supports the central role of hyperuricaemia in its pathogenesis. Larger GWAS are required to identify if variants in inflammatory pathways contribute to progression from AH to gout.

Association between serum urate, gout and comorbidities: a case-control study using data from the UK Biobank.

OBJECTIVES: To examine the association between comorbidities and serum urate (SU), gout and comorbidities, and to determine whether the association between gout and comorbidities is independent of SU. METHODS: We performed a case-control study using UK Biobank data. Two separate analyses were conducted: one excluding participants with gout to investigate the association between comorbidities and SU and the other with participants with gout as the index condition to examine the association between gout and comorbidities. SU was measured at the baseline visit. Self-reported physician-diagnosed illnesses were used to define gout and comorbidities, except for chronic kidney disease (CKD), which was defined using an estimated glomerular filtration rate cut-off. Participants prescribed urate-lowering treatment were also classified as gout. Logistic regression was used to examine associations. Odds ratios (ORs) and 95% CIs were calculated and adjusted for covariates including comorbidities and SU. RESULTS: Data for 458 781 UK Biobank participants were used to examine the association between comorbidities and SU. There was an association between hypertension, ischaemic heart disease (IHD), congestive cardiac failure (CCF), hyperlipidaemia, CKD and SU with and adjusted OR (aOR) of 1.10-3.14 for each 1 mg/dl SU increase. A total of 10 265 gout cases and 458 781 controls were included in the analysis of association between gout and comorbidities. Gout associated independently with hypertension, IHD, CCF, hyperlipidaemia and diabetes, with aORs of 1.21-4.15 after adjusting for covariates including SU. CONCLUSION: Comorbidities associate with increasing SU. The association between gout and cardiometabolic comorbidities was independent of SU, suggesting separate SU-independent mechanisms such as inflammation driven by crystal deposition, pro-inflammatory genotype or non-purine dietary factors.

Brief Report: Monosodium Urate Monohydrate Crystal Deposits Are Common in Asymptomatic Sons of Patients With Gout: The Sons of Gout Study.

OBJECTIVE: To estimate the prevalence and distribution of asymptomatic monosodium urate monohydrate (MSU) crystal deposition in sons of patients with gout. METHODS: Patients with gout were mailed an explanatory letter with an enclosed postage-paid study packet to mail to their son(s) age ≥20 years old. Sons interested in participating returned a reply form and underwent telephone screening. Subsequently, they attended a study visit at which blood and urine samples were obtained and musculoskeletal ultrasonography was performed, with the sonographer blinded with regard to the subject's serum urate level. Images were assessed for double contour sign, intraarticular or intratendinous aggregates/tophi, effusion, and power Doppler signal. Logistic regression was used to examine associations. Adjusted odds ratios (ORadj ) and 95% confidence intervals (95% CIs) were calculated. RESULTS: One hundred thirty-one sons (mean age 43.8 years, mean body mass index 27.1 kg/m2 ) completed assessments. The serum urate level was ≥6 mg/dl in 64.1%, and 29.8% had either a double contour sign or intraarticular aggregates/tophi in ≥1 joint. All participants with MSU deposition had involvement of 1 or both first metatarsophalangeal joints. Intratendinous aggregates were present in 21.4% and were associated with intraarticular MSU crystal deposits (ORadj 2.96 [95% CI 1.17-7.49]). No participant with a serum urate level of ≤5 mg/dl had MSU crystal deposition seen on ultrasonography, and 24.2% of those with serum urate levels between 5 and 6 mg/dl had ultrasonographic MSU deposition. MSU crystal deposition was associated with increasing serum urate levels (ORadj 1.61 [95% CI 1.10-2.36] for each increase of 1 mg/dl). CONCLUSION: Asymptomatic sons of patients with gout frequently have hyperuricemia and MSU crystal deposits. In this study MSU crystal deposits were present in participants with serum urate levels of ≥5 mg/dl. Evaluation of subjects without a family history of gout is needed to determine whether the threshold for MSU crystal deposition is also lower in the general population.

Inflammatory Response in Preterm and Very Preterm Newborns with Sepsis.

The response of the adaptive immune system is usually less intense in premature neonates than term neonates. The primary objective of this study was to determine whether immunological parameters vary between preterm (PT) neonates (≥32 weeks of gestational age) and very preterm (VPT) neonates (<32 weeks of gestational age). A cross-sectional study was designed to prospectively follow PT and VPT neonates at risk of developing sepsis. Plasma concentrations of IFN-γ, TNF-α, IL-6, IL-4, and IL-10 were detected using flow cytometry. C-reactive protein (C-RP) and the complex SC5b-9 were detected in the plasma using commercial kits. A total of 83 patients were included. The laboratory results and clinical histories showed that 26 patients had sepsis; 14 were VPT, and 12 were PT. The levels of C-RP, SC5b-9 (innate immune response mediators), and IL-10 or IL-4 (anti-inflammatory cytokines) were elevated during sepsis in both groups. IFN-γ, TNF-α, and IL-6 (proinflammatory cytokines) were differentially elevated only in PT neonates. The VPT neonates with sepsis presented increases in C-RP, SC5b-9, and anti-inflammatory cytokines but not in proinflammatory cytokines, whereas PT neonates showed increases in all studied mediators of inflammation.