to controls (Figure 2A). Since we did not examine the methylation levels in specific T cells subpopulations, we don’t know what this demethylation in CPA individuals means in term of Th2 LCR activity. The fact that it occurs in this important regulatory region suggests however that the activity of the IL-4 locus might be altered in individuals with history of chronic physical aggression during childhood. On the other end, we found higher methylation in the promoter of STAT6 genes in the CPA individuals (Table 2). STAT6 is a well-known regulator of IL-4 in T cells, specifically in Th2 differentiating cells. As mentioned earlier, it can induce expression of IL-4 by interacting with the Th2 LCR [81] but also by activating the expression of the transcription factor GATA-3 that bind directly to the IL-4 promoter [82]. The methylation differences observed in the promoter of isoform 2 as well as in intron 1 of isoform 1 were validated by pyrosequencing. Intriguingly, we note that the pyrosequencing methylation levels in STAT6 gene are significantly associated with IL-4 levels in plasma, further supporting a regulatory role for these sites in regulation of IL-4 by STAT6. This is consistent with the hypothesis that increased methylation
