SAMD9 is a (epi-) genetically regulated anti-inflammatory factor activated in RA patients

To identify PBMC-expressed genes significant for RA, and to ascertain their upstream regulatory factors, as well as downstream functional effects relevant to RA pathogenesis. We performed peripheral blood mononuclear cells (PBMCs) transcriptome-wide mRNA expression profiling in a case-control discovery sample. Differentially expressed genes (DEGs) were identified and validated in PBMCs in independent samples. We also generated genome-wide SNP genotyping data, and collected miRNA expression data and DNA methylation data from PBMCs of the discovery sample. Pearson correlation analyses were conducted to identify miRNAs/DNA methylations influencing DEG expression. Association analyses were conducted to identify expression-regulating SNPs. The key DEG, SAMD9, which was reported to function as a tumor suppressor gene, was assessed for its effects on T cell proliferation, apoptosis, and inflammatory cytokine expression. A total of 181 DEGs (Fold Change ≥ 2.0, Bonferroni adjusted p ≤ 0.05) were discovered in PBMCs. Four DEGs (SAMD9, CKLF, PARP9, and GUSB), upregulated with RA, were validated independently in PBMCs. Specifically, SAMD9 mRNA expression level was significantly upregulated in PHA-activated Jurkat T cells in vitro, and correlated with 8 miRNAs and associated with 22 SNPs in PBMCs in vivo. Knockdown of SAMD9 could transiently promote Jurkat T cell proliferation within 48 h and significantly induce TNF-α and IL-8 expression in T cells. SAMD9 expression is (epi-) genetically regulated, and significantly upregulated in PBMCs in RA patients and in activated T cells in vitro. SAMD9 might serve as a T cell activation marker but act as an anti-inflammatory factor.