Association of CRP genetic variation and CRP level with elevated PTSD symptoms and physiological responses in a civilian population with high levels of trauma.

OBJECTIVE Increased systemic inflammation is associated with stress-related psychopathology. Specifically, levels of the proinflammatory marker C-reactive protein (CRP) are elevated in individuals with posttraumatic stress disorder (PTSD). Furthermore, single-nucleotide polymorphisms (SNPs) in the CRP gene are associated with CRP level, risk for cardiovascular disease, and obesity. The authors examined whether polymorphisms within the CRP gene and increased CRP levels are associated with PTSD symptoms and fear physiology in a civilian population with high levels of trauma. METHOD Cross-sectional data and DNA samples were collected from 2,698 individuals recruited from an inner-city public hospital that serves a primarily African American, low-socioeconomic-status population. A subgroup of 187 participants participated in further interviews, testing, and physiological measures; of these, 135 were assessed using the fear-potentiated startle paradigm to assess fear-related phenotypes of PTSD. RESULTS One SNP within the CRP gene, rs1130864, was significantly associated with increased PTSD symptoms (N=2,692), including "being overly alert" as the most significant individual symptom (N=2,698). Additionally, CRP genotype was associated with the odds of PTSD diagnosis (N=2,692). This SNP was also associated with increased CRP level (N=137), and high CRP levels (>3 mg/L) were positively associated with PTSD symptoms (N=187) and fear-potentiated startle to a safety signal (N=135). CONCLUSIONS Together, these data indicate that genetic variability in the CRP gene is associated with serum CRP level and PTSD symptom severity, including that of hyperarousal symptoms. Elevated CRP levels were also associated with exacerbated fear-related psychophysiology and PTSD symptom ratings and diagnosis. These findings suggest a potential mechanism by which an increased proinflammatory state may lead to heightened PTSD symptoms.

[1]  C. Kirschbaum,et al.  The impact of sex and menstrual cycle on the acoustic startle response , 2014, Behavioural Brain Research.

[2]  C. Nievergelt,et al.  Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. , 2014, JAMA psychiatry.

[3]  C. Grillon,et al.  Developmental investigation of fear-potentiated startle across puberty , 2014, Biological Psychology.

[4]  A. Wingo,et al.  The association between childhood trauma and lipid levels in an adult low-income, minority population. , 2014, General hospital psychiatry.

[5]  Mark M. Davis,et al.  Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination , 2013, Proceedings of the National Academy of Sciences.

[6]  H. Resnick,et al.  National estimates of exposure to traumatic events and PTSD prevalence using DSM-IV and DSM-5 criteria. , 2013, Journal of traumatic stress.

[7]  Xiangyang Zhang,et al.  PAC1 receptor (ADCYAP1R1) genotype is associated with PTSD's emotional numbing symptoms in Chinese earthquake survivors. , 2013, Journal of affective disorders.

[8]  Rachel E. Goldsmith,et al.  Interpersonal violence, PTSD, and inflammation: potential psychogenic pathways to higher C-reactive protein levels. , 2013, Cytokine.

[9]  Zulkefli Sanip,et al.  Obesity indices and metabolic markers are related to hs-CRP and adiponectin levels in overweight and obese females. , 2013, Obesity research & clinical practice.

[10]  A. M. Bonametti,et al.  Serum Levels of High Sensitive C Reactive Protein in Healthy Adults From Southern Brazil , 2013, Journal of clinical laboratory analysis.

[11]  J. Boscarino,et al.  Predicting PTSD using the New York Risk Score with genotype data: potential clinical and research opportunities , 2013, Neuropsychiatric disease and treatment.

[12]  B. Bradley,et al.  Sex dependent influence of a functional polymorphism in steroid 5‐α‐reductase type 2 (SRD5A2) on post‐traumatic stress symptoms , 2013, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[13]  Thomas C. Neylan,et al.  xaggerated neurobiological sensitivity to threat as a mechanism linking nxiety with increased risk for diseases of aging , 2012 .

[14]  Jin Zhang,et al.  C-reactive protein (CRP) gene polymorphisms, CRP levels and risk of incident essential hypertension: findings from an observational cohort of Han Chinese , 2012, Hypertension Research.

[15]  Jocelyne Bachevalier,et al.  Impaired safety signal learning may be a biomarker of PTSD , 2012, Neuropharmacology.

[16]  B. Bradley,et al.  Differential immune system DNA methylation and cytokine regulation in post‐traumatic stress disorder , 2011, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[17]  T. Lehtimäki,et al.  Polymorphism in the C-reactive protein (CRP) gene affects CRP levels in plasma and one early marker of atherosclerosis in men: The Health 2000 Survey , 2011, Scandinavian journal of clinical and laboratory investigation.

[18]  D. Hellhammer,et al.  Increased peripheral NF-κB pathway activity in women with childhood abuse-related posttraumatic stress disorder , 2011, Brain, Behavior, and Immunity.

[19]  J. Violanti,et al.  C-reactive protein, interleukin-6, and posttraumatic stress disorder symptomology in urban police officers. , 2011, Cytokine.

[20]  T. Neylan,et al.  Transcriptional Control of Monocyte Gene Expression in Post-Traumatic Stress Disorder , 2011, Disease markers.

[21]  B. Bradley,et al.  Posttraumatic stress disorder is a risk factor for metabolic syndrome in an impoverished urban population. , 2011, General hospital psychiatry.

[22]  B. Bradley,et al.  Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor , 2011, Nature.

[23]  B. Bradley,et al.  Impaired fear inhibition is a biomarker of PTSD but not depression , 2010, Depression and anxiety.

[24]  B. Bradley,et al.  Trauma exposure and stress-related disorders in inner city primary care patients. , 2009, General hospital psychiatry.

[25]  G. Hankey,et al.  Polymorphisms of the CRP gene inhibit inflammatory response and increase susceptibility to depression: the Health in Men Study. , 2009, International journal of epidemiology.

[26]  W. Falls,et al.  Chronic stress increases pituitary adenylate cyclase-activating peptide (PACAP) and brain-derived neurotrophic factor (BDNF) mRNA expression in the bed nucleus of the stria terminalis (BNST): Roles for PACAP in anxiety-like behavior , 2009, Psychoneuroendocrinology.

[27]  Michael Davis,et al.  Posttraumatic stress disorder may be associated with impaired fear inhibition: Relation to symptom severity , 2009, Psychiatry Research.

[28]  J. Manson,et al.  Relation of genetic variation in the gene coding for C-reactive protein with its plasma protein concentrations: findings from the Women's Health Initiative Observational Cohort. , 2009, Clinical chemistry.

[29]  K. Ressler,et al.  Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. , 2008, JAMA.

[30]  K. Ressler,et al.  Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. , 2008, Archives of general psychiatry.

[31]  H. Vaudry,et al.  Role of PACAP in the physiology and pathology of the sympathoadrenal system , 2008, Frontiers in Neuroendocrinology.

[32]  U. Schnyder,et al.  Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder. , 2007, Journal of psychiatric research.

[33]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[34]  Andrew H. Miller,et al.  Cytokine-effects on glucocorticoid receptor function: Relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression , 2007, Brain, Behavior, and Immunity.

[35]  C. Carlson,et al.  Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. , 2006, JAMA.

[36]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[37]  H. Hashimoto,et al.  New Insights into the Central PACAPergic System from the Phenotypes in PACAP‐ and PACAP Receptor‐Knockout Mice , 2006, Annals of the New York Academy of Sciences.

[38]  L. Hawkley,et al.  Psychosocial and Behavioral Predictors of Inflammation in Middle-Aged and Older Adults: The Chicago Health, Aging, and Social Relations Study , 2006, Psychosomatic medicine.

[39]  D. Levy,et al.  Contribution of Clinical Correlates and 13 C-Reactive Protein Gene Polymorphisms to Interindividual Variability in Serum C-Reactive Protein Level , 2006, Circulation.

[40]  Joseph A Boscarino,et al.  Posttraumatic Stress Disorder and Physical Illness: Results from Clinical and Epidemiologic Studies , 2004, Annals of the New York Academy of Sciences.

[41]  A. Shirom,et al.  Association of Fear of Terror With Low-Grade Inflammation Among Apparently Healthy Employed Adults , 2004, Psychosomatic medicine.

[42]  R. Yehuda,et al.  Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder , 2004, Biological Psychiatry.

[43]  L. Hansson,et al.  The inflammatory markers C-reactive protein and serum amyloid A in refugees with and without posttraumatic stress disorder. , 2004, Clinica chimica acta; international journal of clinical chemistry.

[44]  A. Steptoe,et al.  Socioeconomic status, C-reactive protein, immune factors, and responses to acute mental stress , 2003, Brain, Behavior, and Immunity.

[45]  J. Pankow,et al.  Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study. , 2001, Atherosclerosis.

[46]  R. Miller,et al.  C-reactive protein and interleukin 6 receptor in post-traumatic stress disorder: a pilot study. , 2001, Cytokine.

[47]  S. Klein,et al.  The effects of hormones on sex differences in infection: from genes to behavior , 2000, Neuroscience & Biobehavioral Reviews.

[48]  Jeani Chang,et al.  Electrocardiogram abnormalities among men with stress-related psychiatric disorders: Implications for coronary heart disease and clinical research , 1999, Annals of behavioral medicine : a publication of the Society of Behavioral Medicine.

[49]  E. Bosmans,et al.  Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events , 1999, Biological Psychiatry.

[50]  J. Boscarino.  Diseases among men 20 years after exposure to severe stress: implications for clinical research and medical care. , 1997, Psychosomatic medicine.

[51]  Abraham Weizman,et al.  Elevated levels of serum interleukin-1β in combat-related posttraumatic stress disorder , 1997, Biological Psychiatry.

[52]  R. Kessler,et al.  Posttraumatic stress disorder in the National Comorbidity Survey. , 1995, Archives of general psychiatry.

[53]  Barbara O. Rothbaum,et al.  Reliability and validity of a brief instrument for assessing post‐traumatic stress disorder , 1993 .

[54]  D. F. Drake,et al.  A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. , 2013, JAMA psychiatry.

[55]  Shili Lin,et al.  Handbook on analyzing human genetic data : computational approaches and software , 2010 .

[56]  E. Siew,et al.  CRP polymorphisms and progression of chronic kidney disease in African Americans. , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[57]  Henry Völzke,et al.  Association of posttraumatic stress disorder with low-grade elevation of C-reactive protein: evidence from the general population. , 2010, Journal of psychiatric research.

[58]  Andrew H. Miller,et al.  Cytokines sing the blues: inflammation and the pathogenesis of depression. , 2006, Trends in immunology.

[59]  N. Breslau.  Gender differences in trauma and posttraumatic stress disorder. , 2002, The journal of gender-specific medicine : JGSM : the official journal of the Partnership for Women's Health at Columbia.

[60]  D. Charney,et al.  The development of a Clinician-Administered PTSD Scale , 1995, Journal of traumatic stress.