PTSD and the klotho longevity gene: Evaluation of longitudinal effects on inflammation via DNA methylation

PSYCHONEUROENDOCRINOLOGY

卷:117

Article

Wolf, Erika J.^1,2  Logue, Mark W.^1,2,3  Zhao, Xiang^1,2  Daskalakis, Nikolaos P.⁴  Morrison, Filomene G.^1,2  Escarfulleri, Shaline¹  Stone, Annjanette⁵  Schichman, Steven A.⁵  McGlinchey, Regina E.^6,7,8  Milberg, William P.^6,7,8  Chen, Cidi⁹  Abraham, Carmela R.^9,10  Miller, Mark W.^1,2 

[1] VA Boston Healthcare Syst, Natl Ctr PTSD, 116B-2,150 South Huntington Ave, Boston, MA 02130 USA

[2] Boston Univ, Dept Psychiat, Sch Med, Boston, MA 02215 USA

[3] Boston Univ, Biomed Genet, Sch Med, Boston, MA 02215 USA

[4] Harvard Med Sch, McLean Hosp, Dept Psychiat, Boston, MA 02115 USA

[5] Cent Arkansas Vet Healthcare Syst, Pharmacogen Anal Lab, Res Serv, Little Rock, AR USA

[6] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA 02130 USA

[7] VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Disorders, Boston, MA 02130 USA

[8] Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA

[9] Boston Univ, Dept Biochem, Sch Med, Boston, MA 02215 USA

[10] Boston Univ, Dept Pharmacol & Expt Therapeut, Sch Med, Boston, MA 02215 USA

关键词: PTSD;    Inflammation;    Methylation;    Accelerated aging;    Klotho;   

DOI  :  10.1016/j.psyneuen.2020.104656

来源: Elsevier

【 摘 要 】

Background: Longevity gene klotho (KL) is associated with age-related phenotypes including lifespan, cardiometabolic disorders, cognition, and brain morphology, in part, by conferring protection against inflammation. We hypothesized that the KL/inflammation association might be altered in the presence of psychiatric stress and operate via epigenetic pathways. We examined KL polymorphisms, and their interaction with posttraumatic stress disorder (PTSD) symptoms, in association with KL DNA methylation in blood. We further examined KL DNA methylation as a predictor of longitudinal changes in a peripheral biomarker of inflammation (C-reactive protein; CRP). Methods: The sample comprised 309 white non-Hispanic military veterans (93.5 % male; mean age: 32 years, range: 19-65; 30 % PTSD per structured diagnostic interview); 111 were reassessed approximately two years later. Results: Analyses revealed a methylation quantitative trait locus at rs9527025 (C370S, previously implicated in numerous studies of aging) in association with a Cytosine-phosphate-Guanine site (cg00129557; B=-.65, p=1.29 x 10(-20)), located within a DNase hypersensitivity site in the body of KL. There was also a rs9527025 x PTSD severity interaction (B=.004, p=.035) on methylation at this locus such that the minor allele was associated with reduced cg00129557 methylation in individuals with few or no PTSD symptoms while this effect was attenuated in those with elevated levels of PTSD. Path models revealed that methylation at cg00129557 was inversely associated with CRP over time (B = -.14, p=.005), controlling for baseline CRP. There was also an indirect effect of rs9527025 X PTSD on subsequent CRP via cg00129557 methylation (indirect B = -.002, p=.033). Conclusions: Results contribute to our understanding of the epigenetic correlates of inflammation in PTSD and suggest that KL methylation may be a mechanism by which KL genotype confers risk vs. resilience to accelerated aging in those experiencing traumatic stress.

【 授权许可】

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