models [11-14], is consistent with social influences on gene expression. Experimental manipulations of long term social behavior may ultimately be required to definitively establish causation in the human clinical setting. What is clear from this study's ancillary analyses is that relationships between gene expression and social isolation cannot be attributed to correlated differences in other known demographic, psychological, social, or medical risk factors (including perceived stress, depression, hostility, socio-economic status, and altered subset distributions within the circulating leukocyte pool). Ancillary analyses controlling for transient variations in loneliness also suggest that the transcriptional correlates of chronic subjective social isolation (trait loneliness) do not stem solely from transient variations in state loneliness. A persistent sense of social isolation appears to represent a distinct epidemiological risk factor that is associated with broad alterations in immune cell gene expression linked to reciprocal shifts in the activity of pro- and anti-inflammatory transcription control pathways.
