Article

Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism

Instituto Gulbenkian de Ciência, R Quinta Grande, 6, 2781-196 Oeiras, Portugal.
Molecular Psychiatry (Impact Factor: 14.5). 04/2004; 9(3):264-71. DOI: 10.1038/sj.mp.4001409
Source: PubMed

ABSTRACT

The role of the serotonin system in the etiology and pathogenesis of autism spectrum disorders (ASD) is not clearly defined. High levels of platelet serotonin (5-HT) have been consistently found in a proportion of patients, and it is known that specific 5-HT transporter gene (SLC6A4) variants modulate transporter reuptake function, therefore possibly influencing the occurrence of hyperserotonemia in a subset of autistic patients. We have examined the association of platelet serotonin levels with two SLC6A4 polymorphisms, 5-HTT gene-linked polymorphic region (HTTLPR) in the promoter and intron 2 variable number of tandem repeats (VNTR), in a sample of 105 ASD patients, their parents, and 52 control children. Quantitative transmission disequilibrium test (QTDT) results showed a significant effect on 5-HT levels of each SLC6A4 marker (P=0.017 for HTTLPR; P=0.047 for intron 2 VNTR) and of haplotypes of the two markers (P=0.017), with a major contribution of the L.Stin2.10 haplotype (P=0.0013). A 5-HT mean value in the range of hyperserotonemia was associated with the homozygous L.Stin2.10 haplotype (H (1,N=97)=7.76, P=0.0054), which occurred in 33% of hyperserotonemic patients against 6% of patients with normal 5-HT levels (Fisher's exact test: P=0.013, OR=8). Allele interaction at the HTTLPR locus was found, with a significant dominance variance effect on 5-HT levels. We found no transmission disequilibrium of any of the SLC6A4 variants in ASD. Our results show that the SLC6A4 gene is a significant factor in the determination of 5-HT levels, and that specific SLC6A4 variants are associated with an increased risk for hyperserotonemia in our sample of autistic patients. The biological mechanism, however, is unlikely to involve the SLC6A4 gene solely. The associated SLC6A4 alleles likely interact with other genes or environmental factors to produce the abnormally high 5-HT levels observed in this subset of autistic patients, who possibly represent a separate etiological group.

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Available from: Celeste Bento, Apr 30, 2014
    • "Accumulating evidences suggest that SLC6A4 variants possibly regulate behavioral phenotype by maintaining the 5-HT level in the CNS. While four studies indicated lack of correlation of 5-HTTLPR with platelet 5-HT content (Anderson et al., 2002; Betancur et al., 2002; Cross et al., 2008; Napolioni et al., 2011), two reports suggested association of 5-HTTLPR and STin2 with increased risk of platelet hyperserotonemia in autism (Coutinho et al., 2004, 2007). However, such studies are lacking in the Indian population. "
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    ABSTRACT: Presence of platelet hyperserotonemia and effective amelioration of behavioral dysfunctions by selective serotonin reuptake inhibitors (SSRI) in autism spectrum disorders (ASD) indicate that irregularities in serotonin (5-HT) reuptake and its homeostasis could be the basis of behavioral impairments in ASD patients. SLC6A4, the gene encoding serotonin transporter (SERT) is considered as a potential susceptibility gene for ASD, since it is a quantitative trait locus for blood 5-HT levels. Three functional polymorphisms, 5-HTTLPR, STin2 and 3'UTR-SNP of SLC6A4 are extensively studied for possible association with the disorder, with inconclusive outcome. In the present study, we investigated association of these polymorphisms with platelet 5-HT content and symptoms severity as revealed by childhood autism rating scale in ASD children from an Indian population. Higher 5-HT level observed in ASD was highly significant in children with heterozygous and homozygous genotypes comprising of minor alleles of the markers. Quantitative transmission disequilibrium test demonstrated significant genetic effect of STin2 allele as well as STin2/3'UTR-SNP and 5-HTTLPR/3'UTR-SNP haplotypes on 5-HT levels, but no direct association with overall CARS score and ASD phenotype. Significant genetic effect of the markers on specific behavioral phenotypes was observed for various sub-phenotypes of CARS in quantitative trait analysis. Even though the 5-HT level was not associated with severity of behavioral CARS score, a significant negative relationship was observed for 5-HT levels and level and consistency of intellectual response and general impression in ASD children. Population-based study revealed higher distribution of the haplotype 10/G of STin2/3'-UTR in male controls, suggesting protective effect of this haplotype in male cases. Overall results of the study suggest that SLC6A4 markers have specific genetic effect on individual ASD behavioral attributes, might be through the modulation of 5-HT content.
    No preview · Article · Sep 2014 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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    • "Remarkably, proteins regulating 5-HT homeostasis peripherally and in the central nervous system (CNS) are largely conserved: the SLC6A4 and HTR2A genes encode the same SERT and 5-HT2A receptor, respectively, both in platelets and brain (Cook et al., 1994; Lesch et al., 1993). Several genes involved in SERT trafficking, especially SLC6A4 and ITGB3, were mapped to autism linkage regions, found to host rare variants causing ASD, or were associated with autism through common variants (Cantor et al., 2005; Coutinho et al., 2004; Napolioni et al., 2011; Stone et al., 2004; Weiss et al., 2004. 2006a). "
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    ABSTRACT: Elevated blood serotonin (5-HT) levels were the first biomarker identified in autism research. Many studies have contrasted blood 5-HT levels in autistic patients and controls, but different measurement protocols, technologies, and biomaterials have been used through the years. We performed a systematic review and meta-analysis to provide an overall estimate of effect size and between-study heterogeneity, while verifying whether and to what extent different methodological approaches influence the strength of this association. Our literature search strategy identified 551 papers, from which 22 studies providing patient and control blood 5-HT values were selected for meta-analysis. Significantly higher 5-HT levels in autistic patients compared to controls were recorded both in whole blood (WB) [O.R.=4.6; (3.1–5.2); P=1.0×10−12], and in platelet-rich plasma (PRP) [O.R.=2.6 (1.8–3.9); P=2.7×10−7]. Predictably, studies measuring 5-HT levels in platelet-poor plasma (PPP) yielded no significant group difference [O.R.=0.54 (0.2–2-0); P=0.36]. Altogether, elevated 5-HT blood levels were recorded in 28.3% in WB and 22.5% in PRP samples of autistic individuals, as reported in 15 and 4 studies, respectively. Studies employing HPLC vs fluorometric assays yield similar cumulative effect sizes, but the former display much lower variability. In summary, despite some limitations mainly due to small study sample sizes, our results significantly reinforce the reliability of elevated 5-HT blood levels as a biomarker in ASD, providing practical indications potentially useful for its inclusion in multi-marker diagnostic panels for clinical use.
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    • "Interestingly, abnormal levels of these cytokines have been reported in cerebrospinal fluid (Pardo et al., 2005) and brain tissue (Li et al., 2009) from an autism patient with motor skill deficits. Recent studies suggested SLC6A4/HTT might be a candidate gene for autism based on the association of hyperserotonemia with autism (Coutinho et al., 2004). Autism patients have been treated with selective serotonin re-uptake inhibitors which appears to reduce repetitive and aggressive behavior (Posey et al., 2008). "
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