Background/Purpose: Systemic Lupus Erythematosus (SLE) is a heterogeneous disease. Interleukin-1 receptor-associated kinase 4 (IRAK4) activity is predicted to affect multiple pathogenic pathways in SLE¹. We hypothesized that coordinated expression of IRAK4-regulated genes reflective of toll-like receptor (TLR) and other upstream stimulation will reflect activity of the pathway. We aimed to identify a TLR7/8-induced gene signature to identify SLE patients who are more likely to respond to the inhibition of the IRAK4 pathway.

Methods: To determine candidate genes, we first identified those with impaired response to TLR7 or 8 stimulation by R848 in patients carrying loss-of-function mutations in IRAK4 (analyzed from GEO: GSE 25742)². We then selected differentially-expressed genes that also showed elevated baseline expression in SLE blood vs. healthy controls in 2 datasets: PBMC microarray data from an extra-renal SLE cohort (SLE n=61, HC=20) and whole blood (WB) RNA sequencing data from a second extra-renal cohort (SLE n=103; HC= 19)³. We then confirmed these genes underwent dose-dependent down-regulation in response to R848 in healthy human WBs treated with selective IRAK4 small molecule inhibitor (SMI) compounds.

Results: Our analysis of the GSE 25742 microarray dataset showed 285 genes that displayed significantly lower induction by R848 in the whole blood from IRAK4-deficient patients vs. healthy controls (FDR<0.05; FC>1.25). The IRAK4-deficient patients did not upregulate type I interferons (IFNs) in response to R848. Baseline levels of 44 differentially-expressed genes were up-regulated in blood from SLE vs. healthy controls in both SLE cohorts analyzed. We further observed that 9 genes were down-regulated in a dose-dependent manner by 2 distinct IRAK4 SMI compounds in the human whole blood assay. These genes formed an inter-correlating signature in SLE patient blood, and partially overlapped with the interferon signature. Significant positive correlations were observed between top candidate genes and ISM status, anti-dsDNA status, and levels of BAFF, anti-RNP and anti-Sm, while significant negative correlations were observed between the candidate genes and levels of C3 and C4 in both SLE datasets.

Conclusion: We have identified a set of IRAK4-dependent genes with an inter-correlating signature and partial overlap with the interferon signature, that could potentially serve as biomarkers of the IRAK4 pathway in SLE patient blood samples.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-irak4-dependent-gene-signature-as-a-biomarker-candidate-for-irak4-small-molecule-inhibitor-in-systemic-lupus-erythematosus/