PhosSNPs-Regulated Gene Network and Pathway Significant for Rheumatoid Arthritis

Abstract

Objectives: Peripheral blood mononuclear cells (PBMCs) are critical for immunity and participate in multiple human diseases, including rheumatoid arthritis (RA). PhosSNPs are nonsynonymous SNPs influencing protein phosphorylation, thus probably modulate cell signaling and gene expression. We aimed to identify phosSNPs-regulated gene network/pathway potentially significant for RA.

Methods: We collected genome-wide phosSNP genotyping data and transcriptome-wide mRNA expression data from PBMCs of a Chinese sample. We discovered and verified with public datasets differentially expressed genes (DEGs) associated with RA, and replicated RA-associated SNPs in our study sample. We performed a targeted expression quantitative trait locus (eQTL) study on significant phosSNPs and DEGs.

Results: We identified 29 nominally significant eQTL phosSNPs and 83 target genes, and constructed comprehensive regulatory/interaction networks, highlighting the vital effects of two eQTL phosSNPs (rs371513 and rs4824675, FDR <0.05) and four critical node genes (HSPA4, NDUFA2, MRPL15, and ATP5O). Besides, two node/key genes NDUFA2 and ATP5O, regulated by rs371513, were significantly enriched in mitochondrial oxidative phosphorylation pathway. Besides, four pairs of eQTL effects were replicated independently in whole blood and/or transformed fibroblasts.

Conclusions: The findings delineated a potential role of protein phosphorylation and genetic variations in RA and warranted the significant roles of phosSNPs in regulating RA-associated genes expression in PBMCs. The results pointed out the relevance and significance of oxidative phosphorylation pathway to RA.

Keywords: Expression quantitative trait locus; Peripheral blood mononuclear cells; Phosphorylation-related SNPs; Rheumatoid arthritis.