These data identify a distinct transcriptional fingerprint of subjective social isolation in human leukocytes, which involves increased basal expression of inflammatory and immune response genes. Bioinformatic analysis of differentially expressed promoters suggests that these effects may be shaped by reduced activity of the anti-inflammatory glucocorticoid transcription control pathway and a complementary increase in activity of the pro-inflammatory NF-κB/Rel pathway. These data provide the first evidence that social-environmental risk factors are linked to global alterations in human gene transcription, and they establish a molecular context for understanding the increased risk of inflammatory disease observed in human beings who experience a chronic sense of subjective social isolation (loneliness). Dissociation between stable circulating cortisol levels and impaired glucocorticoid receptor-mediated transcription highlights the need to analyze social environmental risk at the level of the functional genomic dynamics that ultimately drive the expression of disease.
