We identified stimulus-specific trans networks putatively driven by coding variants. One such example is a trans hub observed at rs1800440, which codes for an amino acid substitution (p.Asn453Ser) in the first exon of CYP1B1, encoding a monocyte-expressed cytochrome P450 enzyme (24). This polymorphism is associated with a reduction in the half-life of CYP1B1 to one-third that of wild type (25) and is a cis-eQTL for CYP1B1 (table S2), consistent with reduced half-life driving a compensatory increase in transcription of the variant allele. Single SNP analysis of rs1800440 identified 43 genes, predominantly implicated in cancer and the inflammatory response, associating in trans after IFN-γ treatment (table S4). This variant shows significant variation in interpopulation allele frequency, the minor allele being very rare in African and Asian populations [fixation index (FST) of 0.288 (P = 0.03) and integrated haplotype score (iHS) of −2.126 for the CEU (Caucasian) HapMap population], suggesting possible selection pressure.
