A further example of a context-specific trans network involving a transcription factor consisted of 23 genes encoding proteins involved in the ubiquitin-proteasome system (34), whose expression was associated with rs2057763 after IFN-γ (fig. S11 and table S4). Twelve of these trans genes encode subunits of the 26S proteasome, including the 20S proteasome core (PSMA1, PSMB2, PSMB4, and PSMB6) together with the 19S regulator complex (PSMC3, PSMC4, PSMC5, PSMD1, PSMD3, PSMD11, PSMD13, and PSMD14), suggesting that this SNP alters the expression of a key proteasomal regulator in response to IFN-γ. IPA revealed that protein ubiquitination was the only significant pathway (P = 9 × 10−20) with two top regulators of this network: NFE2L2 (P = 5.4 × 10−14), encoding Nrf2, a transcription factor that regulates genes containing antioxidant response elements (ARE) in their promoters, and the known Nrf2 inducer molecule 1,2-diothio-3-thione. rs2057763 is an intergenic SNP 36.7 kb from the closest gene on chromosome 7p15 encoding NFE2L3, a relatively poorly characterized NFE2L2 homolog, recently recognized to play a key role in inflammation (35). Probes to NFE2L3 were not analyzed in the
