Session Title: Genetics and Genomics of Rheumatic Disease I
Session Type: Abstract Submissions (ACR)
Background/Purpose: Cia4 is a quantitative trait locus on rat chromosome 7 that regulates disease severity and joint damage in three models of rheumatoid arthritis including pristane-induced arthritis (PIA). To identify cellular and molecular processes regulated by Cia4, we studied the expression over 23,000 genes in synovial tissues from MHC identical DA (severe erosive disease) and DA.F344(Cia4) congenics (mild and non-erosive disease) rats.
Methods: Synovial tissues from DA and DA.F344(Cia4) congenics were collected at pre-clinical (day 10 and day 14 post-pristane administration; qPCR) and recent onset (day 18; microarray and qPCR) stages following the induction of PIA and analyzed for gene expression levels.
Results: Il6 levels were 135-fold higher in DA compared with congenics at very early pre-clinical stages (day 10), and remained significantly increased. The Il6 increase preceded the modest increase in Il1b (4.2-fold) suggesting that Il6 could be driving cytokine expression and the early histologic inflammatory infiltration. 187 genes had significantly different expression and included inflammatory mediators expressed in increased levels in DA such Slpi (10.94‑fold) and its receptor Plscr1 (2.31-fold), Cd163 (5.85-fold), Ccl7 (5.17-fold) and Litaf (2.09-fold). Syk or NFκB pathway activating and interacting genes were increased in DA synovial tissues. Fifty-nine genes implicated in cancer-related phenotypes were increased in DA, while genes involved in cell metabolism, transport across membranes and tissue protection such as Acat1, Dgat1, Dhcr7, Slc25a29, and Slc1a1 were increased in DA.F344(Cia4) congenics. 21 genes differentially expressed, or expressed in only one of the two strains were located within the Cia4 interval, and could be the gene accounting for the arthritis effect.
Conclusion: The Cia4 interval contains a new arthritis gene that regulates early Il6, Il1b expression, and other inflammatory mediators central to arthritis, and processes involved in cancer that could be mediating the development of synovial hyperplasia and invasion, and cartilage and bone destruction.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-arthritis-severity-locus-cia4-is-an-early-regulator-of-il-6-il-1%ce%b2-and-nf%ce%bab-activators-expression-in-pristane-induced-arthritis/