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

Abstract

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 (5-HTTLPR) 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 l variant was associated with more rapid initial platelet 5-HT uptake (Vmax), 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 (Bmax), 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.

Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women

“…Interestingly, recent reports have described polymorphisms in the SERT gene 20 which lead to either up-or downregulation of its expression. Such altered expression has thus far been reported in lymphocytes, platelets, and brain tissue, [21][22][23] and although similar changes have not yet been investigated in the gut, it is possible that they would be found here also. The possibility exists that such polymorphisms may be present in subtypes of IBS patients, and the predicted resultant changes in 5-HT content (recently reported by Moses and colleagues 18 ) or function in these patients may underlie some of their symptomology and indeed response to drugs.…”

13-cis-Retinoic Acid Alters Intracellular Serotonin, Increases 5-HT1AReceptor, and Serotonin Reuptake Transporter LevelsIn Vitro

“…Two functional polymorphisms in the human SERT gene are associated with increased vulnerability to depression and to affect the response to antidepressants (40). These polymorphisms of the SERT gene are associated with reduced SERT expression, reduced 5-HT reuptake rate (20,41,42) and increased susceptibility to depression (20,21,43). Also, SERT-null mice exhibit decreased immobility in the tail suspension test (44) and siRNA knockdown of SERT in adult mice reduced time spent immobile in the forced swim test (45).…”

A Hierarchical Factor Model of Executive Functions in Adolescents: Evidence of Gene-Environment Interplay

“…Because the rare L g and S allele are functionally equivalent, we combined the rs24431 SNP and 5-HTTLPR polymorphism so that the variable had three levels: (1) “S/S,” which includes S/S and S/L g genotypes, (2) “S/L,” which includes S/L a and L g /L a genotypes, and (3) “L/L,” which includes the L a /L a genotype. Following empirical precedent (Greenberg et al, 1999; Little et al, 1998), we dummy coded 5-HTTLPR genotype where individuals carrying at least one copy of the low transcription alleles (i.e., S/S and S/L) were coded 0 and individuals carrying zero low transcription alleles (i.e., L/L) were coded 1. Genotype frequencies did not deviate significantly from Hardy-Weinberg equilibrium (χ 2 = .17; df = 1).…”