ADRA2B polymorphism as a putative biomarker for the acquisition of anxiety based on inadequate storage of emotional memories

Why is one person plagued by memories of traumatic events years after the fact,
while another hardly has any problems? Findings in the field of molecular
biology have indicated that how events are stored in a more emotionally laden
manner is influenced by genetic factors (de Quervain, Kolassa, Ertl, Onyut,
Neuner, Elbert & Papassotiropoulosm, 2007). One of the genes involved in the
regulation of the stress response system is ADRA2B, the gene coding for the a2b
adrenergic receptor. An estimated 30 percent of people carry the 12Glu9 variant
of this gene. This deletion variant codes for a receptor in which 3 glutamic
acid residues (301-303) are missing from its third intracellular loop. This
modification changes a number of essential receptor functions, such as receptor
desensitisation. In a recent study, researchers showed 435 subjects with and
without the deletion variant a variety of images: images with negative
emotional associations (e.g. bloody operation), with positive emotional
associations (e.g. cute children) and neutral images (e.g. someone making a
phone call). People with the deletion variant remembered the emotional
photographs in particular; 78% of the images they remembered had an emotional
association, compared with 43% in people without the deletion variant of the
ADRA2B gene. The researchers wondered whether people with this genetic variant
also ran a higher risk of developing post traumatic stress disorder (PTSD). In
order to test this theory, the genetic profile of 202 Rwandan refugees was
determined. This revealed that refugees with PTSD more frequently carried the
deletion variant of the ADRA2B gene than refugees without PTSD (and without a
history of the condition). They also found that the seriousness of reliving
differed significantly between the two groups suggesting that the deletion
variant acts primarily as a loss-of-function polymorphism of the a2b-adrenergic
receptor in the regulation of emotional memory (de Quervain et al., 2007, p.
1139).
The results of this study provide a biomolecular aetiological explanation for
anxiety disorders. For example, people with the deletion variant of the ADRA2B
gene may run an elevated risk for deregulation of the HPA axis, making them
more vulnerable to stressful impressions and potentially increasing their
chances of developing anxiety.
Dentistry is a particularly suitable context for testing this hypothesis. This
is because dental treatment is experienced as more or less stressful by the
majority of individuals, and there is a significant correlation between nature
and frequency of unpleasant dental experiences and anxiety about dental
treatment (De Jongh, Muris, Ter Horst and Duyx, 1995). There are also large
individual differences in how people react to the same treatment. In a recent
trial, 34 people underwent a certain maxillary surgery (removal of an M3 in the
lower jaw; De Jongh et al, submitted for publication). About 27% of them showed
higher disposition anxiety four weeks after the treatment than they did before
the treatment, while anxiety remained the same or decreased in the rest of the
group. It may be that the memories of the intervention have been stored as more
emotionally laden events in the brains of these individuals, and that this is
caused by a less adequate stress response based on the ADRA2B polymorphism.

The objective of the proposed research is to gain insight into the
circumstances under which anxiety and avoidance behaviour can develop. More
precisely, the goal of the current trial is to determine whether a genetic
basis exists for the individual difference in stress responsiveness and
susceptibility to developing phobic anxiety about dental treatment. To
determine whether the deletion variant of ADRA2B is involved, answers to the
following questions will be sought.

1. Is the deletion variant of ADRA2B more common in individuals being treated
for their extreme anxiety about dental treatment (and who also meet the DSM IV
criteria for a specific phobia, and score > 15 on the Dental Anxiety Scale)
than people without this anxiety?

2. Do people with this variant of ADRA2B have more emotionally laden memories
of previous dental interventions, and do they suffer more from them than people
without this variant?

3. If we expose people to a standard dental experience, do individuals with
this variant respond with more intrusive memories and/or with an increase of
the existing anxiety level than people without this variant?

The study is a pre-test and post-test with control group design and takes place
according to the criteria set out in the Declaration of Helsinki. Potential
study subjects are approached and asked to participate in the study. The nature
and goal of the study is explained to the them, and if they agree to
participate, they are asked to sign an informed consent form. Subjects are
informed that research data will be collected anonymously, that their name and
other personal details cannot in any way be traced back to individual findings,
and that all collected data will be destroyed after being interpreted.
Subjects will receive an envelope with a number of questionnaires, a test tube
with a fixative liquid and a cotton swap prior to a standard dental treatment
(anaesthesia, preparation and application of a filling). They are asked to
collect cheek mucosa with the cotton swab and place it in the appropriate test
tube. They then receive an envelope containing a number of questionnaires,
namely the:
* Dental Anxiety Scale (DAS), to measure the level of disposition anxiety for
the dental treatment;
* Level of Exposure Questionnaire (Vragenlijst angstwekkende gebeurtenissen,
VAG), to measure the frequency of previous unpleasant/shocking events, both
dental and otherwise;
* Impact of Events Scale, Revised (IES-R), to measure trauma symptoms
(reliving, avoidance, hyperarousal);
Also included is a brief questionnaire with items about the overall number of
memories, the number of positive and negative memories about past dental
treatment. Subjects are asked to determine the intensity of the most
representative memory, to recall the clarity of the memory, the feeling of
*nowness* and the degree to which this memory influences the respondent*s daily
life (VAS).
After completing the questionnaires, they are offered dental treatment, and the
dentist is asked to describe the technical details of the procedure on a
separate form.
Once treatment is complete, participants are once again asked to complete a
short questionnaire asking them about anxiety and tension during treatment, how
they experienced pain, and the intensity of the memory of the treatment.
Subsequently a final discussion takes place, and the completed forms and test
tube with cheek mucosa are placed back in the envelope and sealed. If they
wish, people may speak to a psychologist.

not applicable