title: Serotonin transporter promoter variants in autism: functional effects and relationship to platelet hyperserotonemia.
abstract: The well-replicated platelet hyperserotonemia of autism has stimulated interest in serotonin (5-HT) in autism. We have examined the effects of the serotonin transporter gene (5-HTT, locus SLC6A4) promoter polymorphism (5-HTTLPR) on platelet 5-HT physiology in autism. Platelet 5-HT uptake rates and affinities (V(max) and K(m)), uptake site densities (B(max)) and 5-HT levels were examined in 31 French individuals with autism genotyped with respect to the 5-HTTLPR. Platelet 5-HT uptake and 5-HT levels were measured using HPLC; uptake sites were determined by radioligand binding. A 1.5-fold increased rate (V(max)) of platelet 5-HT uptake was observed in ll genotype individuals compared to those with ls and ss genotypes (Mann- Whitney U-test, P = 0.022). However, no significant relationship was observed between genotype and uptake site density (U-test, P = 0.51). Although median levels of platelet 5-HT in platelet-rich plasma were higher in the ll group, only trend level significance was observed (U-test, P= 0.069); platelet 5-HT content measured in whole blood was similar across genotypes. Uptake rates were well correlated with B(max) values (r = 0.66, P = 0.002); correlations between uptake and platelet 5-HT levels and between B(max) values and 5-HT levels were somewhat lower. While 5-HTTLPR alleles had an appreciable effect on platelet 5-HT uptake rates, effects on 5-HT levels and uptake site density were smaller or absent. Based on these preliminary data and prior studies of allele frequencies, we conclude that the 5-HTTLPR is not a major determinant of the group mean platelet serotonin elevation seen in autism. However, a role for increased uptake in the hyperserotonemia of autism can not be ruled out. In addition, it appears that studies of platelet 5-HT measures in autism and other disorders should take account of the effects of 5-HTTLPR genotype on 5-HT uptake
authors.affiliation: Dept of Child Psychiatry, Child Study Center, Yale University School of Medicine, 230 S Frontage Road, New Haven, CT 06510, USA. george.anderson@yale.edu
authors.forename: George M
authors.initials: GM
authors.lastname: Anderson
authors.forename: L
authors.initials: L
authors.lastname: Gutknecht
authors.forename: D J
authors.initials: DJ
authors.lastname: Cohen
authors.forename: S
authors.initials: S
authors.lastname: Brailly-Tabard
authors.forename: J H M
authors.initials: JH
authors.lastname: Cohen
authors.forename: P
authors.initials: P
authors.lastname: Ferrari
authors.forename: P L
authors.initials: PL
authors.lastname: Roubertoux
authors.forename: S
authors.initials: S
authors.lastname: Tordjman
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000097:blood* / Q000235:genetics*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D015283:Citalopram / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D012701:Serotonin / Q000097:blood* / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D015283:Citalopram; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human