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Central Serotonin Transporter Availability Measured with [ 123I]β-CIT SPECT in Relation to Serotonin Transporter Genotype

van Dyck, Christopher H.; Malison, Robert T.; Staley, Julie K.; Jacobsen, Leslie K.; Seibyl, John P.; Laruelle, Marc; Innis, Robert B.; Gelernter, Joel; Baldwin, Ronald M.; Buckley, P. F.

Objective: A functional polymorphism has been described in the promoter region of the gene (SLC6A4) coding for the serotonin transporter protein (SERT). This polymorphism has two common alleles that have been designated as long (l) and short (s). Each allele has been linked with a number of human clinical phenotypes, including neuropsychiatric diseases associated with dysregulation of serotonin (5-HT) transmission. In vitro studies of non-neural cells have suggested that the l-allele may have higher transcriptional activity than the s-allele. However, the relevance of these findings for SERT levels in brain remains unclear. Method: We assessed genotype at the SLC6A4 promoter polymorphism in 96 healthy European American subjects (age range 18 to 88) who also underwent SPECT scanning with [123I]2ß-carbomethoxy-3ß-(4-iodophenyl)tropane ([123I]ß-CIT) for measurement of central SERT protein availability. A ratio of specific to nondisplaceable brain uptake (i.e., V3" = [brainstem-diencephalon – occipital]/occipital), a measure proportional to the binding potential (Bmax/KD), was derived. Results: The results showed that the main effect of genotype was significant (F=4.48, df=2,92, p=0.014, ANCOVA, age = covariate). Post-hoc Tukey pairwise comparisons revealed that the ss-homozygotes had significantly greater SERT availability than the ls-heterozygotes (p=0.024). In addition, there was a nonsignificant trend for the ll-homozygotes to have greater SERT availability than the heterozygotes (p=0.092), but no difference was observed between the ll-homozygotes and ss-homozygotes (p=0.70). The effect of age was significant in the ANCOVA model (t=–3.61, df=95, p<0.001). Conclusions: These results do not suggest higher central SERT levels in association with the l-allele in European American subjects but point to a more complex relationship between SLC6A4 genotype and protein availability.

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