Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets

The human serotonin transporter (5-HTT), encoded by a single gene on chromosome 17q11.2, is expressed in brain and blood cells. 5-HTT is implicated in mood and anxiety regulation, and is where antidepressant and antianxiety drugs initially act in the brain. A 5-HTT-linked promoter region (5HTTLPR) insertion]deletion polymorphism with long (l) and short (s) forms affects transporter expression and function. The s variant reduced 5-HTT gene transcription in a reporter gene construct and human lymphoblasts, resulting in reduced transporter levels and 5-HT uptake, acting as a dominant allele. In this study, we investigated the expression and function of 5-HTT in platelets from healthy male volunteers. The I variant was associated with more rapid initial platelet 5-HT uptake (V(max)), the index of platelet 5- HTT function most clearly heritable, while the s allele was dominant. The 5- HTTLPR genotype had no effect on platelet [³H]paroxetine binding (B(max)), affinity for [³H]5-HT or [³H]paroxetine, or 5-HT content. The 5-HT uptake findings support a functional difference in the two 5-HTTLPR variants, reinforcing their attractiveness as candidate genes in neuropsychiatric research.