Yeo, A. et al. Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women. Gut 53, 1452-1458

Novartis Pharmaceuticals Corporation, USCDMA, One Health Plaza, East Hanover, NJ 07936-1080, USA.
Gut (Impact Factor: 14.66). 11/2004; 53(10):1452-8. DOI: 10.1136/gut.2003.035451
Source: PubMed


Serotonin (5-hydroxtryptamine, 5-HT) is an important factor in gut function, playing key roles in intestinal peristalsis and secretion, and in sensory signalling in the brain-gut axis. Removal from its sites of action is mediated by a specific protein called the serotonin reuptake transporter (SERT or 5-HTT). Polymorphisms in the promoter region of the SERT gene have effects on transcriptional activity, resulting in altered 5-HT reuptake efficiency. It has been speculated that such functional polymorphisms may underlie disturbance in gut function in individuals suffering with disorders such as irritable bowel syndrome (IBS). The aim of this study was to assess the potential association between SERT polymorphisms and the diarrhoea predominant IBS (dIBS) phenotype.
A total of 194 North American Caucasian female dIBS patients and 448 female Caucasian controls were subjected to genotyping.
Leucocyte DNA of all subjects was analysed by polymerase chain reaction based technologies for nine SERT polymorphisms, including the insertion/deletion polymorphism in the promoter (SERT-P) and the variable tandem repeat in intron 2. Statistical analysis was performed to assess association of any SERT polymorphism allele with the dIBS phenotype.
A strong genotypic association was observed between the SERT-P deletion/deletion genotype and the dIBS phenotype (p = 3.07x10(-5); n = 194). None of the other polymorphisms analysed was significantly associated with the presence of disease.
Significant association was observed between dIBS and the SERT-P deletion/deletion genotype, suggesting that the serotonin transporter is a potential candidate gene for dIBS in women.

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Available from: David Alpers, Sep 16, 2014
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    • "Case–control studies about 5-HTTLPR were conducted to verify this hypothesis. Some studies demonstrated a positive association between this polymorphism and IBS [10,11], while another study failed to confirm this association [12]. A meta-analysis of 8 studies conducted in 2007 tried to reach a definite conclusion and showed a negative result [13]. "
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    ABSTRACT: The results of previous studies assessing the association between the 5-HTTLPR polymorphism of serotonin transporter gene and irritable bowel syndrome (IBS) are inconsistent. The aim of this study was to clarify the association between the 5-HTTLPR mutation and the presence of IBS and its subtypes with a meta-analysis of 25 studies. A thorough search for case-control studies evaluating the association between the 5-HTTLPR polymorphism of serotonin transporter gene and the presence of IBS was carried out in four electronic databases. A meta-analysis was performed in accordance with the Cochrane Handbook for systemic reviews. A total of 25 articles with 3443 IBS cases and 3359 controls were included into our meta-analysis. No significant association was found between this polymorphism and IBS in all populations. Whereas the LL genotype was demonstrated to be a risk factor for constipation predominant IBS (IBS-C) development in the overall population (LL vs SS: OR = 1.570, 95%CI = 1.147-2.148, P = 0.005, Bon = 0.030; LL vs LS: OR = 1.658, 95%CI = 1.180-2.331, P = 0.004, Bon = 0.024; LL vs LS/SS: OR = 1.545, 95%CI = 1.187-2.012, P = 0.001, Bon = 0.006). In the analysis of different ethnicities, L allele and LL genotype were significantly associated with increased IBS-C risk in the East Asian population (L vs S: OR = 1.487, 95%CI = 1.139-1.941, P = 0.003, Bon = 0.018; LL vs SS: OR = 2.575, 95%CI = 1.741-3.808, P = 0.000, Bon = 0.000; LL vs LS: OR = 3.084, 95%CI = 2.017-4.715, P = 0.000, Bon = 0.000; LL vs LS/SS: OR = 2.759, 95%CI = 1.933-3.938, P = 0.000, Bon = 0.000), but not in the Caucasian population. Different from the conclusions of the earlier meta-analyses, the 5-HTTLPR mutation affects IBS-C but not IBS-D and IBS-M development and this effect only exists in the East Asian population but not other populations.
    BMC Gastroenterology 02/2014; 14(1):23. DOI:10.1186/1471-230X-14-23 · 2.37 Impact Factor
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    • "A second SERT polymorphism, variable numbe of tandem repeats (VNTR) STin2, located in intron 2 and consisting of a variable number (usually 9, 10, or 12) of nearly identical 17-bp segments, had been found to be associated with IBS in one study, with the 10/12 genotype more frequent in Chinese patients than in controls [8]. Most authors, however, had found no association between STin2 VNTRs and IBS [3], [9], [10]. "
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    ABSTRACT: Irritable bowel syndrome (IBS) is a common clinical gastrointestinal dysfunction disorders. 5-sertonon (5-hydroxytryptamine, 5-HT) is a very important neurotransmitter, which is involved in gastrointestinal motion and sensation. Solute carrier family 6 member 4 (SLC6A4) gene encode serotonin transporter (SERT) which function is to rapidly reuptake the most of 5-HT. Therefore, it is needed to explore the association between SLC6A4 gene polymorphisms and IBS. 119 patients and 238 healthy controls were administrated to detect the SLC6A4 gene polymorphisms including 5-HT-transporter-gene-linked polymorphic region (5-HTTLPR), variable number of tandem repeats (VNTRs) and three selected tag Single Nucleotide Polymorphisms (SNPs) rs1042173, rs3794808, rs2020936 by using polymerase chain reaction (PCR) and TaqMan® SNP Genotyping. There were significant difference for 5-HTTLPR between IBS and control groups (X2 = 106.168, P<0.0001). In control group, genotypes were mainly L/L (58.4%), however, the genotypes in IBS were S/S (37.8%). The significant difference was shown in D-IBS subjects when compared to the controls (X(2) = 50.850, P<0.0001) for 5-HTTLPR. For STin2 VNTR, rs1042173, rs3794808, and rs2020936 polymorphisms, there were no any significant differences between IBS and control groups. There were no statistical significantly haplotypes for 5-HTTLPR, VNTRs and the three SNPs between IBS and controls. The S allele in 5-HTTLPR was a susceptible allele with Chinese Han IBS, but other associations of VNTRs, three selected Tag SNPs and positive haplotype with IBS were not found. It is indicated that much research are needed to study the relationship between other polymorphisms in SLC6A4 gene and IBS.
    PLoS ONE 01/2014; 9(1):e84414. DOI:10.1371/journal.pone.0084414 · 3.23 Impact Factor
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    • "Sex differences in the central pathophysiology of IBS have been reported.34,35 A significant association has been observed between female patients with IBS-D and polymorphisms in the serotonin-reuptake transporter protein, suggesting that the serotonin transporter is a potential candidate gene for IBS-D in women.36,37 However, it is not known whether differences in serotonin-reuptake transporter polymorphisms between women and men with IBS contribute to the observed differences in clinical response to 5-HT3-receptor antagonists.23 "
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    ABSTRACT: Irritable bowel syndrome (IBS) is a functional disease with persisting gastrointestinal symptoms that has been classified into four subtypes. Serotonin (5-hydroxytryptamine [5-HT]) plays important physiological roles in the contraction and relaxation of smooth muscle. Intraluminal distension of the intestine is known to stimulate the release of endogenous 5-HT from enterochromaffin cells, activating 5-HT3 receptors located on primary afferent neurons and leading to increases in intestinal secretions and peristaltic activity. Ramosetron, a potent and selective 5-HT3-receptor antagonist, has been in development for use in patients suffering from diarrhea-predominant IBS. In a double-blind, placebo-controlled, parallel-group study of 418 patients with diarrhea-predominant IBS-D, once-daily 5 μg and 10 μg doses of ramosetron increased the monthly responder rates of IBS symptoms compared to placebo. In a 12-week randomized controlled trial of 539 patients, a positive response to treatment was reported by 47% of a once-daily 5 μg dose of ramosetron-treated individuals compared to 27% of patients receiving placebo (P<0.001). Furthermore, the responder rate was increased in the oral administration of 5 μg of ramosetron for at least 28 weeks (up to 52 weeks), and long-term efficacy for overall improvement of IBS symptoms was also demonstrated. The rate was further increased subsequently. Adverse events were reported by 7% in ramosetron treatment. No serious adverse events, eg, severe constipation or ischemic colitis, were reported for long-term treatment with ramosetron. In conclusion, further studies to evaluate the long-term efficacy and safety of ramosetron are warranted in the form of randomized controlled trials.
    Clinical and Experimental Gastroenterology 07/2013; 6(1):123-8. DOI:10.2147/CEG.S32721
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