Socio-economic status covaries with central nervous system serotonergic responsivity as a function of allelic variation in the serotonin transporter gene-linked polymorphic region
Introduction
A 44-bp insertion/deletion polymorphism in the 5′ regulatory region of the serotonin transporter (5-HTT) gene may be associated with behavioral phenotypes as diverse as anxiety-related personality traits, various psychopathologies (e.g., affective disorders, alcoholism, bulimia nervosa, autism), late onset Alzheimer’s disease, and cardiovascular reactions to psychological stress (Lesch et al., 1996, Collier et al., 1996, Cook et al., 1997, Li et al., 1997, Oliveira et al., 1998, Rosenthal et al., 1998, Hallikainen et al., 1999, Di Bella et al., 2000, Williams et al., 2001). However, attempts to replicate behavioral associations in the 5-HTT gene-linked polymorphic region (5-HTTLPR) have occasioned both success and failure (e.g., Ball et al., 1997, Ebstein et al., 1997, Klauck et al., 1997, Rees et al., 1997, Esterling et al., 1998, Hoehe et al., 1998, Gelernter et al., 1998, Jorm et al., 1998, Mazzanti et al., 1998, Ohara et al., 1998, Ricketts et al., 1998, Rosenthal et al., 1998, Deary et al., 1999, Flory et al., 1999, Frisch et al., 1999, Gustavsson et al., 1999, Murakami et al., 1999, Zhong et al., 1999, Benjamin et al., 2000, Hu et al., 2000, Jorm et al., 2000, Kunugi et al., 2000, Mann et al., 2000, Osher et al., 2000, Melke et al., 2001, Mossner et al., 2001, Tordjman et al., 2001, Tsai et al., 2001, Yirimya et al., 2001, Steffens et al., 2002). Reasons for these inconsistencies remain unclear, but may entail a variety of methodological differences among studies, such as variability in participant age, sex, and ethnicity, concomitant psychiatric morbidity or other sources of sample heterogeneity, limited statistical power, or differences in study design.
Located ~1 kb upstream of the coding sequence of the 5-HTT gene on chromosome 17q11.2, the 5-HTTLPR contains functional variation known to modulate activity of the 5-HTT gene promoter. Relative to the longer variant of this biallelic repeat, the deletion, or short, allele reduces transcriptional efficiency by about twofold when fused to a luciferase reporter gene and transfected into human placental choriocarcinoma (JAR) cells (Lesch et al., 1996, Heils et al., 1996). In cultured lymphoblasts, the short allele is associated with lower 5-HTT mRNA production and decreased serotonin uptake (Lesch et al., 1996). Other studies addressing functional properties of the 5-HTTLPR are informative as well, although not always consistent. For instance, the short allele may be associated with lower midbrain 5-HTT mRNA expression and transporter availability (Little et al., 1998, Heinz et al., 2000), reduced uptake of serotonin into platelets (Greenberg et al., 1999, Nobile et al., 1999), and lower whole blood serotonin content (Hanna et al., 1998), but these findings are not reported in all studies (Willeit et al., 2001, Stoltenberg et al., 2002, Kaiser et al., 2002). In accord with reduced serotonin turnover in brain, cerebrospinal fluid (CSF) concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), may be lower in persons homozygous for the short allele, but again, this association was seen in only one of two investigations (Jonsson et al., 1998, Williams et al., 2001). Each of two other recent studies suggest that neuroendocrine responses to pharmacologic challenges that enhance serotonergic neurotransmission also vary by 5-HTTLPR genotype. Women homozygous for the short allele, for instance, exhibited smaller elevations in plasma prolactin concentration (i.e. diminished central serotonergic responsivity) on acute administration of clomipramine, an inhibitor of neuronal serotonin reuptake, relative to women carrying two copies of the long allele (Whale et al., 2000). In the second study, males having at least one short variant of the promoter polymorphism also showed a blunted prolactin response to the 5-HT releasing agent, fenfluramine, compared to men likewise homozygous for the long allele (Riest et al., 2001).
Length variation in the 5-HTTLPR of rhesus monkeys (Macaca mulatta) has been described as well (Lesch et al., 1997, Bennett et al., 2002). The rhesus polymorphism (rh5-HTTLPR) is similarly biallelic, and as in humans, luciferase reporter gene constructs containing the short allele demonstrate reduced in vitro transcriptional efficiency. Interestingly, the short allele is also associated with lower CSF 5-HIAA concentrations in rhesus macaques, but only among peer-reared (as opposed to mother-reared) monkeys (Bennett et al., 2002). Peer-rearing constitutes a model of early maternal deprivation that presages developmental abnormalities persisting into adulthood (Higley et al., 1992). These findings suggest that environmental adversity moderates effects of allele-dependent variation in 5-HTT activity on brain serotonergic function. Analogous interactions might conceivably account, in part, for apparent inconsistencies among prior studies involving human subjects, in which study populations often vary markedly. First, however, it may be asked whether attributes of the environment or subject characteristics moderate effects of 5-HTTLPR variation on central nervous system (CNS) serotonergic activity in humans. In a nonpatient sample of community volunteers, we recently observed that rises in plasma prolactin concentration elicited by fenfluramine challenge are attenuated among subjects of lower socio-economic status (SES) (as indexed by income and educational attainment), compared to persons of more advantaged social position (Matthews et al., 2000). In this paper, we report that this association varies in magnitude as a function of allelic variation in the 5-HTTLPR, with lower socio-economic status predicting diminished central serotonergic responsivity only among individuals carrying the short allele of this regulatory polymorphism.
Section snippets
Subjects
Subjects were participants in the University of Pittsburgh Cholesterol and Risk Evaluation (CARE) project, a study of the neurobehavioral correlates of plasma lipid concentrations, and were recruited via locally distributed brochures, posters and media advertisements. Exclusion criteria included an age younger than 24 or older than 60 years; lifetime history of Bipolar I or psychotic symptoms, cancer, stroke, insulin-dependent diabetes, chronic kidney or liver disease; use of psychotropic,
Preliminary analyses
To determine whether 5-HTTLPR genotype or sex of subject influenced common correlates of the fenfluramine-induced PRL response, two-way (Genotypel/l,l/s,s/s×Sexm,f) analyses of variance were conducted on several relevant variables. Baseline PRL concentrations varied somewhat by Genotype (F2,133=3.1, p<0.05), but did not differ between men and women or by interaction of Genotype and Sex. Mean log-Baseline PRL values of l/l, l/s, and s/s subjects were 1.9 (SD=0.47; M[g]=6.7 ng/ml), 1.8 (0.44; 6.0
Discussion
In the present study, individual differences in socio-economic status predicted CNS serotonergic responsivity (as shown previously (Matthews et al., 2000)) among community volunteers administered an abbreviated fenfluramine challenge. However, this relationship was qualified by allelic variation in the promoter region of the 5-HTT gene. Individuals of lower income and less education showed an attenuated PRL response to fenfluramine, relative to those ranked higher on these indices, but only
Acknowledgements
Preparation of this manuscript was supported by National Institutes of Health grants HL-40962 (SBM), HL-46328 (MFM), and HL-65137 (SBM).
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