Background/Purpose: Rheumatoid arthritis (RA) is a pathologically heterogeneous disease with multiple contributing factors. Many models have been developed to study RA severity and progression, and several RA severity signatures have been derived. However, the molecular mechanisms underlying these RA severity signatures are not fully understood. For example, Cia25 congenic rat interval regulates arthritis severity. The congenic region is conserved among mouse, rat, and human. However, which gene or genes in the congenic region regulate RA severity and which molecular mechanisms remains incompletely understood. We recently developed a human molecular causal network for RA. We leveraged the RA network to elucidate potential molecular mechanisms that drive RA severity.

Methods: A gene expression signature comparing Cia25 congenic and parental strains was collected. A candidate gene list including HIP1 was derived by comparative genomic analysis of mouse, rat, and human genome and comparing SNPs between Cia25 congenic and parental strains.

Results: Cia25 congenic signature was projected to the human RA network that we constructed. We derived a Cia25 congenic subnetwork by using the signature as seeds and collecting nodes that were within 2 hops from the seeds. We compared the subnetwork with GO biological pathways, and found genes involved in immune response, cell adhesion, and cell migration pathways were significantly enriched in the subnetwork. We further compared transcription factor (TF) binding sites in promoter regions of genes in the subnetwork and known TF binding motifs, and found binding sites for transcription factors BACH1 and BACH2 were enriched in the subnetwork. Bach1 has been shown to regulate osteoclast in mouse models. BACH2 was identified a GWAS as a candidate gene for RA susceptibility. It is worth to note that one of the candidate genes for the Cia25 congenic strain is HIP1. In the RA network, HIP1 was regulated by STK3 and STK3 was a part of Cia25 congenic subnetwork. The HIP1 subnetwork (including genes that can be reached from HIP1 within 3 hops) significantly overlapped with the Cia25 congenic subnetwork, supporting HIP1 as a potential candidate for Cia25 congenic strain. For proof of concept we knockdown HIP1 in human fibroblast-like synoviocytes and detected significantly reduced cell invasiveness.

Conclusion: We used a new RA synovial gene network to help identify new arthritis regulatory genes by integrating complex datasets and show that this strategy led to validation and discovery of new arthritis susceptibility and severity genes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/an-integrative-rheumatoid-arthritis-network-for-elucidating-molecular-mechanisms-underlying-ra-severity/