Although child abuse has been associated with adult PTSD, genetic factors have also been known to contribute to the development of the disorder. Can interplay between child abuse and gene polymorphisms related to stress response help predict those at greater risk of PTSD symptoms during adulthood? The short answer is “yes,” according to a study in the March 19 JAMA.

“A central question in research on PTSD is why some individuals are more likely than others to develop the disorder in the face of similar levels of trauma exposure,” said Elisabeth B. Binder, MD, PhD, Assistant Professor in the Department of Psychiatry and Behavioral Sciences and the Department of Human Genetics at Emory University in Atlanta, and colleagues.

The researchers conducted a study to determine the role of polymorphisms in FKBP5, a gene involved in glucocorticoid receptor–mediated stress response, in predicting PTSD symptoms in a highly traumatized population. They also studied whether these genetic variations interacted with increasing levels of both child abuse and other types of trauma exposure to predict PTSD symptoms during adulthood.

AT RISK FOR PTSD

Genetic and psychological risk factors were examined in 900 patients seeking care in general medical care and obstetrics-gynecology clinics of an urban public hospital between 2005 and 2007. Primary outcome measures included severity of adult PTSD symptomatology, as measured by the modified PTSD Symptom Scale during the previous two weeks; non–child abuse trauma, as measured using the Traumatic Events Inventory for lifetime history of exposure to trauma; and child abuse trauma, as measured using both the Traumatic Events Inventory and the Childhood Trauma Questionnaire to determine level of abuse and neglect. Eight single nucleotide polymorphisms (SNPs) from the FKBP5 locus were genotyped. DNA was extracted from saliva and was available for 762 of the 900 participants.

Among all subjects, the mean age was 40.8 (range, 18 to 81); 42.7% were male, and 95.2% self-identified themselves as African American. Approximately two-thirds (67.5%) were unemployed, 22.8% were receiving disability benefits, and 31.4% reported a household monthly income of less than $250. At least one “significant trauma” was reported by 84.9% of all study participants (89.6% of males; 81.3% of females). Overall, 37.2% reported that they were attacked with a knife, gun, or other weapon by someone other than a spouse, romantic partner, or boyfriend/girlfriend; this was higher among men (54.5%) than women (24.2%). An additional 30.5%, overall, reported being attacked without a weapon by someone other than a spouse, romantic partner, or boyfriend/girlfriend. Levels of PTSD symptoms were “as high or higher than the rates of PTSD we see in very recently returned combat veterans,” said the researchers.

CHILDHOOD TRAUMA–GENE INTERACTION

Level of non–child abuse trauma and level of child abuse trauma each separately predicted PTSD symptoms in adults. The mean modified PTSD Symptom Scale score increased from 8.03 for the 566 participants who reported no child abuse to 14.65 for the 189 participants who reported either physical or sexual abuse and to 20.93 for the 54 participants who reported both physical and sexual child abuse.

Although genetic variations did not directly predict PTSD symptom outcome or interact with level of non–child abuse trauma to predict PTSD symptom severity, four SNPs in the FKBP5 locus—rs9296158, rs3800373, rs1360780, and rs9470080—significantly interacted with severity of child abuse to predict level of PTSD symptoms in adults. This gene-environment interaction remained significant when the investigators controlled for depression severity scores, age, sex, levels of trauma exposure other than child abuse, and genetic ancestry.

“The most novel and important finding of our study was the interaction between FKBP5 polymorphisms and child abuse history to predict the levels of adult PTSD symptoms,” noted the researchers. “These genotypes potentially serve as predictors of both risk and resilience for adult PTSD among survivors of child physical and sexual abuse.

“Interestingly, the genotypes previously associated with a higher number of previous depressive episodes and faster response to antidepressant treatment [rs3800373 and rs1360780] were the genotypes with the highest level of adult PTSD symptoms in the presence of child abuse,” they wrote. “Our study is the first to our knowledge to provide evidence directly supporting a developmental or symptom-dependent difference in the functional consequences of these FKBP5 SNPs on glucocorticoid-receptor sensitivity.”

Coinvestigator Rebekah G. Bradley, PhD, said that the results of their study, which demonstrate one way in which the experience of childhood abuse may impact stress response processes, may provide clues as to why some psychotherapeutic treatments and drug therapies used for PTSD work for some patients but not others.

OPENING THE DOOR TO MORE RESEARCH

Studies examining the association between genetic polymorphisms, the environment, and a specific disease and its symptoms are “just the door opening,” said Catherine D. DeAngelis, MD, MPH, Editor-in-Chief of JAMA. She asked, “Suppose you could go to your doctor and say, ‘I want my human genome. I want it examined, and I want to know all the things I’m at risk for.’ Would you want it?”

Dr. DeAngelis, Professor of Pediatrics at Johns Hopkins University School of Medicine, Baltimore, noted that of about 130 manuscripts considered for the March 19 JAMA theme issue on genetics and genomics, none reported on genetic causality—ie, akin to the BRCA1 and BRCA2 breast and ovarian cancer susceptibility genes. “It’s a simplistic way of saying it, but ‘this causes that or this can cause that’ is quite different than ‘is associated with.’ The next step is to let’s see what the causality is.”

THE IMPORTANCE OF APPLYING KNOWLEDGE TO CLINICAL PRACTICE

In another study published in the JAMA theme issue, Maren T. Scheuner, MD, MPH, a practicing medical geneticist, and colleagues found that a large gap exists between knowledge of genomic medicine and incorporation of this knowledge into clinical practice for common chronic diseases. She and her colleagues reported results of a review of the medical literature between January 2000 and February 2008, which identified 68 articles assessing four key areas of genomic medicine for common diseases: outcomes, consumer information needs, delivery of genomic medicine, and challenges and barriers to integration of genomic medicine.

One key to integration is determining what value genetic details might add to patient care, said Dr. Scheuner, a researcher at the RAND Corporation in Santa Monica, California. “In terms of risk assessment, do results from genetic tests really help us identify people that we wouldn’t have identified otherwise? Will we end up treating them differently? It takes complex study designs to gather all of this information to answer these questions,” she said.

Most of the studies found that the process of genetic counseling and testing for diseases actually decreased worry, stress levels, negative mood, and anxiety and depression, even in those found to have a gene mutation associated with increased risk. “There were some short-lived negative psychological effects, but generally with follow-up, after four to six months, those effects went back to baseline,” she said. In addition, “in some studies, but not all, there seemed to be improved accuracy of perceived risk for developing disease. If people have an understanding of their risks, they may be more motivated to enter into appropriate screening or prevention protocols.”

The researchers also found that concerns about privacy, including who might have access to information, and the potential for discrimination by health insurers and employers were some of the issues raised by patients.

“It will be a lost opportunity if the health services research components of genomic medicine fail to keep pace with the rapid basic science advances and clinical discoveries,” they concluded.

—Debra Hughes

Suggested Reading
Binder EB, Bradley RG, Liu W, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299(11):1291-1305.
Scheuner MT, Sieverding P, Shekelle PG. Delivery of genomic medicine for common chronic adult diseases: a systematic review. JAMA. 2008;299(11):1320-1334.

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