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. 2018 Jan:67:194-202.
doi: 10.1016/j.bbi.2017.08.022. Epub 2017 Sep 1.

CRP polymorphisms and DNA methylation of the AIM2 gene influence associations between trauma exposure, PTSD, and C-reactive protein

M W Miller  1 , H Maniates  2 , E J Wolf  3 , M W Logue  4 , S A Schichman  5 , A Stone  5 , W Milberg  6 , R McGlinchey  6
Affiliations

CRP polymorphisms and DNA methylation of the AIM2 gene influence associations between trauma exposure, PTSD, and C-reactive protein

M W Miller et al. Brain Behav Immun. 2018 Jan.

Abstract

Background: Recent studies have implicated inflammatory processes in the pathophysiology of posttraumatic stress disorder (PTSD). C-reactive protein (CRP) is a widely-used measure of peripheral inflammation, but little is known about the genetic and epigenetic factors that influence blood levels of C-reactive protein (CRP) in individuals with PTSD.

Methods: Participants were 286 U.S. military veterans of post-9/11 conflicts (57% with current PTSD). Analyses focused on single nucleotide polymorphisms (SNPs) in the CRP gene and DNA methylation at cg10636246 in AIM2-a locus recently linked to CRP levels through results from a large-scale epigenome-wide association study.

Results: PTSD was positively correlated with serum CRP levels with PTSD cases more likely to have CRP levels in the clinically-elevated range compared to those without a PTSD diagnosis. Multivariate analyses that controlled for white blood cell proportions, genetic principal components, age and sex, showed this association to be mediated by methylation at the AIM2 locus. rs3091244, a functional SNP in the CRP promoter region, moderated the association between lifetime trauma exposure and current PTSD severity. Analyses also revealed that the top SNPs from the largest genome-wide association study of CRP conducted to date (rs1205 and rs2794520) significantly interacted with PTSD to influence CRP levels.

Conclusions: These findings provide new insights into genetic and epigenetic mechanisms of inflammatory processes in the pathophysiology of PTSD and point to new directions for biomarker identification and treatment development for patients with PTSD.

Keywords: AIM2; CRP; DNA methylation; Inflammation; PTSD.

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Figures

Figure 1
Figure 1
cg10636246 mediates the association between current PTSD severity and serum CRP levels Results of the structural equation model that examined the direct and indirect associations between PTSD severity, methylation at the AIM2 locus, and CRP levels controlling for age, sex, the six WBC estimates, and the first three ancestry PCs. In contrast to the significant association between PTSD and CRP levels observed in bivariate analyses (i.e., Table 1: r = .170, p = .004), in this model, the association between PTSD and CRP fell to nonsignificant, indicating that their relationship was mediated by cg10636246. Consistent with this, a test of the indirect effect of PTSD on CRP via cg10636246 (i.e., the mediated path) was statistically significant (std β = .04, p = .017).
Figure 2
Figure 2
CRP SNP rs3091244 Moderates the Association Between Lifetime Trauma Exposure and PTSD Severity Scatterplot depicting the influence of rs3091244 on the relationship between trauma exposure and PTSD severity. This association was significantly stronger for homozygote (2 copy) carriers of the minor allele ([n = 35]; r = .681, p < .001) than for carriers of the major allele ([1 copy, n = 89] r = .364, p < .001; [2 copies, n = 77] r = .323, p = .004).
Figure 3
Figure 3
CRP SNPs rs1205 & rs2794520 Moderate the Association Between PTSD severity and Serum CRP Levels Scatterplot depicting the influence of the two SNPs in perfect LD (rs1205 & rs2794520) that moderated the association PTSD severity and serum CRP level. Decomposition of the interaction showed that the main effect of PTSD severity on CRP was driven exclusively by those who were homozygous for the major allele of both SNPs (CC [n = 84]; r = .364, p = .001; AC [n = 94] r = .022, p = .834; AA [n = 18] r = −.293, p = .239).
Figure 4
Figure 4
Linkage disequilibrium between the 11 CRP SNPs. Note: From 1000 genomes-Phase 3, EUR sample (1000 Genomes Project Consortium et al., 2012)
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