Abstract
Currently, it remains difficult to identify which SNPs identified by GWAS are functional, and how various functional SNPs (fSNPs) interact and contribute to disease susceptibility. GWAS have identified a CD40 locus that is associated with rheumatoid arthritis (RA). We previously used two techniques developed in our lab, SNP-seq and FREP-MS, to determine that the RA risk gene RBPJ regulates CD40 expression via a fSNP at the RA-associated CD40 locus. In the present work, by applying the same approach, we report the identification of 6 proteins that regulate RBPJ expression via binding to two fSNPs on the RA-associated RBPJ locus. Using these findings, together with published data, we constructed an RA-associated signal transduction and transcriptional regulation network (STTRN) that functionally connects multiple RA-associated risk genes via transcriptional regulation networks linked by CD40-induced NF-kB signaling. Remarkably, this STTRN provides insight into the potential mechanism of action for the histone deacetylase (HDAC) inhibitor givinostat, an approved therapy for systemic juvenile idiopathic arthritis (SJIA). Thus, generation of disease-associated STTRNs based on post-GWAS functional studies is demonstrated as a novel and effective approach to apply GWAS for mechanistic studies and target identification.
Transcriptional regulation network analysis of the hypertension-perturbed nucleus tractus solitarius