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C-reactive protein: A stress diathesis marker at the crossroads of maladaptive behavioral and cardiometabolic sequelae.

Several stress-triggered conditions have been linked with systemic inflammation, with previous reports of elevation in plasma levels of the inflammation marker C-reactive protein (CRP) in associationwith childhood adversity (1), depression (2), andposttraumatic stress disorder (PTSD) (3). In this issue, Michopoulos et al. (4) examine whether single-nucleotide polymorphisms (SNPs) within the CRP gene and elevated CRP levelsareassociatedwithPTSDsymptomsandfearphysiologyin a poor, highly traumatized, primarily African American sample recruited from an inner-city public hospital. The authors found one SNP within the CRP gene, rs1130864, to be associated with PTSD diagnosis and greater symptom severity—most significantlythesymptomsofhyperarousal—inasampleofnearly2,700 subjects. In a smaller subsample (fewer than 200 subjects) in whom plasma CRP levels were measured, this SNP was also associatedwithCRP levels, andhighCRP levels (.3mg/L)were positively associated with PTSD symptoms, greater odds of a PTSD diagnosis, and increased psychophysiological hyperarousalasdeterminedbyincreasedfear-potentiatedstartle.After thoughtfully discussing a number of caveats in interpretation of the data, the authors conclude that inflammationmight be a target for PTSD therapeutics. This elegantwork,whilehighlighting apossibly important role for inflammation in PTSD, also illustrates the complexity of untangling the directionality of causal pathways underlying previously reported associations of cardiometabolic disorders and PTSD (5, 6). Although directionality of association of elevatedplasmaCRPwithPTSDcannot be inferred fromMichopoulos and colleagues’ cross-sectional study, the observed association of CRP genotype with PTSD risk suggests a direct etiological link. A recent longitudinal study in U.S.Marines showedthathigherpredeploymentCRPlevelwas associated with greater risk for subsequent PTSD (3). Despite the fact that the prospective nature of an observation diminishes the likelihood of reverse causality, it is nonetheless possible that one or more factors—environmental (e.g., smoking, obesity) and/or genetic—that increase CRP levels are also associatedwith increasedPTSDrisk,withno guarantee thatCRP (as an index of inflammatory processes) plays a causal role in such a pathway. One way to disentangle cause and effect, once larger data sets are available,may be to applyMendelian randomizationanalysis (7).Mendelianrandomizationisa form of instrumental variable analysis that takes advantage of the fact that genes are randomlyassorted fromparents tooffspring and, as such, are transmitted independently of confounding factors and cannot be subject to reverse causation (that is, germlinegeneticvariants that influenceCRPlevelscouldcause PTSD but not vice versa) (8). An even greater challenge to the interpretation of the findings of Michopoulos et al. is the likely impact of unmeasured confounders. The authors note that they lacked information for their sample about comorbid medical illness andobesity (bodymass index).ThehighCRP levelswith large variation they report (mean55.14, SD54.77) may be due in part to a preponderance of individuals with inflammation attributable to chronic medical conditions (e.g., pulmonary, cardiovascular, metabolic), which are increased among those with PTSD (9, 10). In addition, elevated CRP levels have been reported in depression (2), and becausecomorbiddepressive symptoms are not reported in theMichopoulos et al. study, it is not possible to tease out differential effects for depression and PTSD. But the question of specificity goes well beyond comorbiditywith depression. A recentmeta-analysis of 14,991 subjects spanning 36 samples found trauma exposure to be positivelyassociatedwithproinflammatorymarkers, including CRP, interleukin (IL)-1b, IL-6, and tumor necrosis factor-a, across psychiatric diagnoses (11). Future prospective studies comparing inflammatoryprofiles betweensubjectsdeveloping PTSD (5), depression (12), and other stress-related mental disorders—which should be stratified for prenatal and postnatal early adversity (13)—may permit directional and perhaps causal inferences about proinflammatory mechanisms underlying the elevated physical morbidity and mortality observed with these disorders. Validatingadirectcausalgeneticassociationwould implicate an immune/inflammatory mechanism in PTSD pathogenesis. However, even ifCRPelevation is secondary, itmay represent an important potential prognostic marker and therapeutic target. Looking at the cardiovascular literature may prove instructive: Patient-levelmeta-analysis demonstrates continuous The importance of this line ofresearchultimatelyhinges on what it can tell us about treatment.