Background/Purpose: The transcriptomic changes accompanying the transition from asymptomatic hyperuricemia to gout are currently unknown but may be important for identifying and understanding important molecular triggers of gout. We tested the hypothesis that gene expression differences would be seen between whole blood from individuals with gout versus normouricemic and hyperuricemic (non-gout) controls.

Methods: Peripheral blood samples were collected (directly into PAXgene RNA tubes) from 13 gout patients, 3 normuricemic and 3 hyperuricemic controls from the gout Rheumatology Database and Repository (RADAR) at the University of Alabama at Birmingham. Whole blood mRNA was isolated using poly A selection and the transcriptome was sequenced. Sequences were quality controlled and then aligned to the genome using the Spliced Transcripts Alignment to a Reference (STAR) software package.  We tested for fold change differences in mRNA content between controls and gout cases using the R statistical computing package DESeq2.

Results: RNA sequencing yielded an average of 25 M reads per sample with an average read length of 125 bases. Forty eight gene transcripts were significantly differentially expressed (P value < 0.05), after correction for multiple testing, between gout cases and controls (normouricemic plus hyperuricemic). Of these differentially expressed gene transcripts, six that were overexpressed in gout compared to controls (Transcobalamin 1-TCN1, Amine oxidase-AOC1, Matrix metallopeptidase 8-MMP8, Cysteine rich secretory protein 3-CRISP3, Secretory leukocyte peptidase inhibitor-SLPI and Olfactomedin 4-OLFM4) are known to be involved in neutrophil degranulation. Another notable transcript significantly upregulated in gout cases was the S100 calcium binding protein A8-S100A8, which is associated with the production of reactive oxygen species (ROS). Transmembrane protein 176B-TMEM176B, was significantly downregulated in gout cases compared to controls.

Conclusion: The upregulation of genes that implicate pathways representing neutrophil biology (degranulation and ROS production) is consistent with the known role of neutrophils in gout pathogenesis. It is possible that this reflects true differences in the neutrophil gene expression program of gout-affected individuals compared to hyperuricemic and/or normouricemic controls. Reduced expression of TMEM176B has been shown to associate with activation of the NLRP3 inflammasome. Our whole transcriptomic study in gout patients and controls highlights the central role of inflammatory cell activation in the pathogenesis of gout.

« Back to 2019 ACR/ARP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/whole-blood-rna-sequencing-study-of-gout-cases-and-controls-demonstrates-transcriptomic-differences-with-relevance-to-inflammatory-cell-activation/