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. 2022 Apr;39(4):323-333.
doi: 10.1002/da.23247. Epub 2022 Mar 21.

Methylation of the AIM2 gene: An epigenetic mediator of PTSD-related inflammation and neuropathology plasma biomarkers

Sage E Hawn  1   2 , Zoe Neale  1   2 , Erika J Wolf  1   2 , Xiang Zhao  1   2 , Meghan Pierce  2   3   4 , Dana Fein-Schaffer  1 , William Milberg  3   4 , Regina McGlinchey  3   4 , Mark Logue  1   2   5   6 , Mark W Miller  1   2
Affiliations

Methylation of the AIM2 gene: An epigenetic mediator of PTSD-related inflammation and neuropathology plasma biomarkers

Sage E Hawn et al. Depress Anxiety. 2022 Apr.

Abstract

Background: Posttraumatic stress disorder (PTSD) is associated with inflammation and various forms of chronic disease. The Absent in Melanoma 2 (AIM2) gene has been implicated in mechanisms of inflammation and anxiety, and methylation at a particular locus in this gene (cg10636246) has previously been shown to influence the association between PTSD and elevated C-reactive protein levels in blood.

Method: We tested if this association might extend to other indicators of inflammation and to plasma-based measures of neuropathology in a cohort of post-9/11 US military veterans. Using a Bayesian approach, mediation models were tested cross-sectionally (n = 478) and longitudinally (n = 298). Peripheral markers of inflammation and neuropathology were measured with ultra-sensitive Single Molecule Array (Simoa®) technology.

Results: Analyses revealed indirect effects of PTSD symptom severity on peripheral indices of both inflammation (interleukin [IL]6, IL-10, tumor necrosis factor-α; indirect standardized [std.] ß range = 0.018-0.023, all p-values adjusted for multiple testing [padj ] < 0.05) and neuropathology (neurofilament light [NFL]; indirect std. ß = -0.018, padj = 0.02) via AIM2 methylation. This indirect effect was also evident when predicting IL-10 at a follow-up assessment (indirect std. ß = -0.018, padj = 0.04) controlling for baseline IL-10.

Conclusions: Given that AIM2 methylation mediated the association between PTSD symptoms and multiple inflammatory and neuropathology markers, our results suggest that AIM2 methylation may offer clinical utility for indexing risk for adverse health outcomes associated with these peripheral indices of inflammation and neuropathology. Results also suggest a possible shared etiology underlying the frequent co-occurrence of inflammation and neuropathology.

Keywords: DNA methylation; PTSD; inflammation; neuropathology; single molecule array.

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Figures

FIGURE 1
FIGURE 1
Bayesian structural equation model examining the T1 direct cross-sectional associations between PTSD severity, AIM2 methylation, and inflammation (a) and neuropathology (b) markers controlling for age, sex, white blood cell type estimates, and the first three ancestry PCs (covariate effects not shown for simplicity). Values represent standardized beta coefficients and standard deviation of the posterior estimates (in parentheses). *p < 0.05. Posterior predictive p-values for model A = 0.136. 95% CI observed and replicated χ2 = −1.422, 34.699. Test of the indirect effects of PTSD on IL-10 (std. ß = 0.018, padj = 0.04), IL-6 (std. ß = 0.023, padj < 0.001), and TNF -ɑ (std. ß = 0.019, padj = 0.02) via cg10636246 (i.e., the mediated paths) were statistically significant. Posterior predictive p-values for model B = 0.500. 95% CI observed and replicated χ2 = −17.364, 25.018. The indirect effect of PTSD on NFL (std. ß = −0.018, padj = 0.02) via cg10636246 (i.e., the mediated path) was statistically significant but the mediated path for GFAP was not (std. ß = −0.014, p = 0.08)
FIGURE 2
FIGURE 2
Bayesian structural equation model examining the longitudinal associations between T1 PTSD severity, T1 AIM2 methylation, and T2 inflammation (a) and T2 CRP (b) markers controlling for T1 levels of these analytes, age, sex, white blood cell type estimates, and the first three ancestry PCs (demographic and methodological covariates not shown for simplicity). Values represent standardized beta coefficients and standard deviation of the posterior estimates (in parentheses). *>p < 0.05. Posterior predictive p-values for model A = 0.125. 95% CI observed and replicated χ2 = −18.409, 56.097. Posterior predictive p-values for model B = 0.000. 95% CI observed and replicated χ2 = 5.437, 36.941. A test of the indirect effect of PTSD on residualized change in IL-10 via cg10636246 (i.e., the mediated path) was statistically significant (std. ß = −0.022, padj = 0.04). A test of the indirect effect of PTSD on residualized change in CRP via cg10636246 (i.e., the mediated path), was not statistically significant (std. ß; = −0.006, p = 0.450)
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