Does 5‐HTTLPR genotype influence willingness to participate in panic challenges?

Serotonin (5-hydroxytryptamine, 5-HT) is a major modulator of emotional behaviour and influences normal fear as well as pathological anxiety. The serotonin transporter (5-HTT) regulates serotonergic activity by terminating the serotonin action via uptake of this neurotransmitter from the synaptic cleft and is the target for selective serotonin reuptake inhibitor class of antidepressant/antianxiety drugs. A length polymorphism of the human 5-HTT gene (SLC6A4), based on a 44 bp deletion in the upstream promoter region, with two relatively common variants, a long or a short allele, has been studied intensively and is supposed to be functional. Several population-based association studies report an association between the short allele of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) and increased anxiety-related personality traits. However, so far it is unknown how possibly aversive conditions and stressful implications of a panic challenge may influence the 5HTTLPR genotype composition and the associated psychological traits of a study sample. We screened potential male participants for study participation by advertisement in the general population, i.e. they were asked to take medication for several weeks and to undergo two panic challenges. It is important to clarify that this study is not concerned with any effects of the medication or panic challenges per se (which are the subject of another study) but merely with the genotype and personality variables of the recruited population (assessed before any pharmacological manipulation). Two hundred male Caucasian volunteers applied to participate in the study. The study protocol was approved by the local ethics committee and each subject gave informed consent. Volunteers were furthermore assessed with three different psychometric scales for personality traits: The ‘‘Anxiety Sensitivity Index’’, the X2 (trait) scale of the ‘‘State–Trait Anxiety Inventory’’, and the neuroticism subscale of the ‘‘NEO Five-Factor-Inventory’’. Venous blood was collected from each subject, and genomic DNA was isolated using the QIAamp DNA Blood Mini Kit (Qiagen; Hilden, Germany). Polymerase chainreaction-based genotyping was performed with primer sequences described previously. The amplified products were resolved on 2% agarose gels and visualized with ethidium bromide. Gel photographs were independently read by two investigators, and fragment sizes were determined by comparison to molecular length standards. We observed a 450-bp fragment corresponding to the long allele and a 406-bp fragment corresponding to the short allele. All genotyping was done blind to the diagnostic assessment. Genotype analysis revealed allele frequencies of 0.61 for the long and 0.39 for the short allele, respectively. The genotype frequencies of the 5-HTTLPR in our sample were 10.5% (short/short), 41.5% (long/short), and 48% (long/long), respectively. In comparison to previous population-based association studies with a predominantly Caucasian sample, such as large the study (n 5 847) by short/short frequency: 17%], the proportion of subjects carrying the short/short genotype was significantly lower in our sample (test of parameter equality between two binominal distributions: z 5 2.02, Po.05). On the basis of the expected frequencies of long and short alleles [0.57 and 0.43, respectively, we found significant differences between the observed and the expected genotype frequency distributions (w test; w 5 23.9, Po.005). Therefore, the genotype distribution does not obey the Hardy–Weinberg equilibrium. This is not surprising, given our population was self-selected and hence does not represent an ideal population. Table 1 presents the average scores of the anxiety-related scales for subjects with the three 5-HTTLPR genotypes. In line with other studies, which suggest that the long allele of the 5-HTTLPR is dominant, statistical analyses were