Effects of chronic interpersonal stress exposure on depressive symptoms are moderated by genetic variation at IL6 and IL1β in youth

Abstract

Aims: Close to one third of patients with major depression show increases in pro-inflammatory cytokines, which are in turn associated with risk for inflammatory disease. Genetic variants that enhance immune reactivity may thus enhance inflammatory and depressive reactions to stress. The aim of the present study was to investigate a trio of functional SNPs in the promoter regions of IL6 (-174G>C, rs1800795), IL1β (-511C>T, rs16944), and TNF (-308G>A, rs1800629) as moderators of the relationship between chronic stress exposure and elevations in depressive symptoms.

Methods: Participants were 444 Australian youth (mean age=20.12) whose exposure to chronic stress in the past 6months was assessed using the semi-structured UCLA Life Stress Interview, and who completed the Beck Depression Inventory II at ages 15 and 20. Between ages 22 and 25, all participants in the selected sample provided blood samples for genotyping.

Results: In line with a hypothesized moderation effect, -174G allele carriers at IL6 had fewer depressive symptoms following interpersonal stress, relative to C/C homozygotes with equal interpersonal stress exposure. However, IL6 genotype did not moderate the effects of non-interpersonal stress exposure (i.e., financial, work and health-related difficulties) on depression. Also in line with hypotheses, the -511C allele in IL1β, previously associated with higher IL-1β expression, was associated with more severe depression following chronic interpersonal stress exposure, relative to T/T homozygotes. Again, the moderating effect was specific to interpersonal stressors and did not generalize to non-interpersonal stress. TNF was not a moderator of the effects of either interpersonal or non-interpersonal stress on later depression outcomes.

Conclusion: Findings were consistent with the hypothesis that pro-inflammatory genetic variation increases the risk of stress-induced depression. The present results provide evidence of a genetic mechanism contributing to individual differences in depressive symptomatology following interpersonal stress exposure.

Keywords: Adolescent depression; Depression; Gene–environment interaction; IL1β; IL6; Pro-inflammatory cytokines; TNF.

Fig. 1

Allelic variation at -174G>C in IL6 moderated the relationship between chronic interpersonal stress in the 6 months prior to age 20 and depressive symptoms at age 20 (β = -.14, p = .02). The slope of the regression line for CC homozygotes (solid line) was significantly different from the slope of the regression line for GG homozygotes (dotted line) (b = -0.98, SE = 0.42, p = 0.02). There was a marginally significant contrast in the slopes of the regression lines for CC homozygotes compared to heterozygotes (dashed line) (b = -0.58, SE = 0.31, p = 0.07). At the same levels of chronic interpersonal stress, CC homozygotes showed higher depressive symptoms compared to GG homozygotes.

Fig. 2

Allelic variation at -511 C>T in IL1β moderated the relationship between chronic interpersonal stress in the 6 months prior to age 20 and depressive symptoms at age 20 (β = 0.13, p = .022). The slope of the regression line for TT homozygotes (solid line) was marginally different from the slope of the regression line for CC homozygotes (dotted line) (b = 0.88, SE = 0.45, p = .053). There was also a marginally significant contrast in the slopes of the regression lines for TT homozygotes and heterozygotes (dashed line) (b = 0.59, SE = 0.31, p = .060).