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Abstract Number: 2837

Asymptomatic Monosodium Urate Crystal Deposition Associates with Increased Expression of Pro-Inflammatory Genes

Gabriela Sandoval-Plata1, Kevin Morgan 2, Tamar Guetta-Baranes 2, Ana Valdes 3, Michael Doherty 4 and Abhishek Abhishek 5, 1Human Genomics and Molecular Genetics, School of Life Sciences, University of Nottingham / Academic Rheumatolog, School of Medicine, University of Nottingham, Nottingham, England, United Kingdom, 2Human Genomics and Molecular Genetics, School of Life Sciences, University of Nottingham, Nottingham, England, United Kingdom, 3Academic Rheumatology, School of Medicine, University of Nottingham / Nottingham NIHR BRC, Nottingham UK, Nottingham, England, United Kingdom, 4Academic Rheumatology, Division of Rheumatology,School of Medicine, University of Nottingham, Nottingham, UKArthritis Research UK Pain Centre, Nottingham, UKNational Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham, UK, Nottingham, England, United Kingdom, 5Academic Rheumatology, School of Medicine, University of Nottingham,Nottingham,UK National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham,UK, Nottingham, England, United Kingdom

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: genetics, hyperuricemia, inflammation and gout

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Session Information

Date: Tuesday, November 12, 2019

Session Title: 5T112: Metabolic & Crystal Arthropathies II: Genetics & Physiology (2834–2839)

Session Type: ACR Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Persistent hyperuricaemia is a prerequisite for gout. However, only 10% of people with hyperuricaemia develop symptomatic gout, whereas 25-35% have asymptomatic monosodium urate (MSU) crystal deposits. Whether these asymptomatic deposits are truly inert, or exert a sub-clinical pro-inflammatory effect is unknown. Since the immune response in gout is mediated primarily by the NLRP3 inflammasome, we hypothesized that the presence of MSU crystals in people with hyperuricaemia but no previous gout flares will initiate changes in the expression of inflammasome-associated genes.

Methods: Individuals recruited into the study were screened for serum urate (SU) levels and presence of MSU crystals within joints by ultrasonography. They were divided into 3 groups: (a) normal SU (< 360µmol/L) without MSU deposits; (b) high SU ( >360µmol/L) without MSU deposits; and (c) high SU with MSU deposits. Peripheral blood was collected in PAXgene blood RNA tubes and total RNA was extracted according to the manufacturer’s protocol. Quantitative RT-PCR was used to analyse the expression of 86 inflammasome and toll-like receptors (TLRs)-associated genes using a customised QIAGEN RT2 Profiler Array. Data were normalised to RPLP0, and the 2-ΔΔCT method was used to calculate fold changes. Differences in relative expression among groups were evaluated using the Kruskal-Wallis H test. P values were corrected for multiple testing using a false discovery rate of 5%. Genes were clustered into four groups, specifically NLRP3 inflammasome-assembly mechanisms, TLRs, NLRP3 inflammasome-effector mechanisms, and inflammasome down-regulators, to evaluate their variation across normouricaemia, hyperuricaemia, and hyperuricaemia with MSU crystal deposits. The models were evaluated using linear regression.

Results: After RNA extraction and cDNA synthesis, 92 samples passed the quality control parameters and underwent the expression profiling. There were 31 participants in the normouricaemic group, 44 in the hyperuricaemia only group, and 17 in the hyperuricaemia with MSU crystal deposit group. Out of 86 genes, 13 showed a significant difference among groups (adjusted p value < 0.05). However, only BIRC2, CD40LG, CXCL1, IL-1β, MEFV, NLRP12, PANX1, TNFSF14 and XIAP had a large upregulation (fold change >1.5) in at least one of the high SU groups, compared to the normal SU group (Figure 1). IL-1β had the largest fold changes in both high SU without MSU crystals and high SU with MSU crystals (1.9 and 3.3 respectively). Moreover, from the four gene-groups, the TLRs gene cluster showed the highest R2 (0.458), followed by the NLRP3 inflammasome-effector mechanism (R2=0.371), the R2 for inflammasome-assembly mechanisms and inflammasome negative regulators were 0.244 and 0.233 respectively.

Conclusion: The differences in the expression of immune-associated genes observed in this study suggest that initial MSU crystal deposition within joints, although asymptomatic, initiates the activation of pro-inflammatory mechanisms. These results only reflect systemic responses on gene-expression, and cytokine assay is underway. Further studies are needed to validate these results in synovial fluid samples.

Figure 1. Significant fold changes relative to the normouricaemic group. Relative mRNA levels were evaluated by quantitative RT-PCR. The expression was normalised to RPLP0 gene and compared among groups using the Kruskal-Wallis H test. FDR 5% was used to correct for multiple testing. Note there was not a significant difference between normal SU and high SU without crystal deposits in all genes. *p=0.01, **p=0.001, ***p<0.0001.


Disclosure: G. Sandoval-Plata, None; K. Morgan, None; T. Guetta-Baranes, None; A. Valdes, None; M. Doherty, None; A. Abhishek, AstraZeneca, 2, Ironwood Pharmaceuticals, 2.

To cite this abstract in AMA style:

Sandoval-Plata G, Morgan K, Guetta-Baranes T, Valdes A, Doherty M, Abhishek A. Asymptomatic Monosodium Urate Crystal Deposition Associates with Increased Expression of Pro-Inflammatory Genes [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/asymptomatic-monosodium-urate-crystal-deposition-associates-with-increased-expression-of-pro-inflammatory-genes/. Accessed August 9, 2022.
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