Cis-eQTL that regulate transcription factor abundance may generate associations in trans to transcription factor target genes (8, 19, 22, 28, 29). We report a significant context-specific trans gene hub to chromosome 4q35 tagged by rs13149699. This SNP displayed a strong stimulus-specific cis association with IRF2, encoding the transcription factor IRF2. Carriage of the A allele of rs13149699 resulted in LPS-induced up-regulation of IRF2 expression, whereas the G allele was associated with coincident suppression of expression. IFN-γ stimulation caused up-regulation of both IRF2 alleles, although more markedly so in A allele carriers (P = 6.9 × 10−32) (Fig. 4A). The ENCODE data set (30) shows that rs13149699, which is located in an intergenic region 57 kb telomeric to IRF2 (Fig. 4B), is spanned by a deoxyribonuclease I (DNase I) hypersensitive site in primary CD14+ monocytes and binds a cluster of transcription factors including REL-A (nuclear factor κB p65) (fig. S10). In the stimulated cells, this SNP is associated with a major trans network, and on single SNP analysis, more than 300 trans genes were defined in the complete data sets (Fig.
