Abstract
The aims of this study were to investigate the relationship of genetic polymorphisms of the serotonin reuptake transporter and the clinical subtypes of irritable bowel syndrome and its influence on the efficacy of tegaserod in Chinese irritable bowel syndrome patients with constipation. Genetic polymorphisms were analyzed in 87 patients and 96 controls, then 41 irritable bowel syndrome patients with constipation received tegaserod for 4 weeks. The primary efficacy variable was the responder rate measured by Subject's Global Assessment of Relief. Secondary efficacy assessed the changes of individual symptoms weekly. There was no significant difference in genotype frequencies between the patients as a whole and the control group. The frequency of the L/L genotype in the serotonin transporter gene-linked polymorphic region was significantly higher in patients with constipation than in controls (25.0% vs. 7.3%). Responder rates to tegaserod were significantly higher in the S/S (85.0%) and L/S (70.0%) than in the L/L genotype (36.4%). All secondary variables also significantly improved in the S/S and L/S groups compared to the L/L group. This study suggests the hypothesis that individuals with the L/L genotype are vulnerable to development of irritable bowel syndrome with constipation, and patients with the L/L genotype respond poorly to treatment with a routine dose of tegaserod.
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Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Muller-Lissner SA (1999) Functional bowel disorders and functional abdominal pain. Gut 45 (Suppl II):II43–II47
Cremonini F, Talley NJ (2005) Irritable bowel syndrome: epidemiology, natural history, health care seeking and emerging risk factors. Gastroenterol Clin North Am 34:189–204
Lau EM, Chen FK, Ziea ET, Chan CS, Wu JC, Sung JJ (2002) Epidemiology of irritable bowel syndrome in Chinese. Dig Dis Sci 47:2621–2624
Park MI, Cammilleri M (2005) Genetic and genotypes in irritable bowel syndrome: Implication for diagnosis and treatment. Gastroenterol Clin North Am 34:305–317
Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531
Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66:2621–2624
Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL (1999) Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelet. Am J Med Genet 88:83–87
Mortensen OV, Thomassen M, Larsen MB, Whittemore SR, Wiborg O (1999) Functional analysis of a novel human serotonin transporter gene promoter in immortalized raphe cell. Brain Res Mol Brain Res 68:141–148
Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwim GM, Smith CA (1996) Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet 347:731–733
Mackenzie A, Quinn J (1999) A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc Natl Acad Sci USA 96:15251–15255
Hranilovic D, Stefulj J, Schwab S, Borrmann-Hassenbach M, Albus M, Jernej B, Wildenauer D (2004) Serotonin transporter promoter and intron 2 polymorphisms: relationship between allelic variants and gene expression. Biol Psychiatry 55:1090–1094
Yeo A, Boyd P, Lumsden S, Saunders T, Handley A, Stubbins M, Knaggs A, Asquith S, Taylor I, Bahari B, Crocker N, Rallan R, Varsani S, Montgomery D, Alpers DH, Dukes GE, Purvis I, Hicks GA (2004) Association between a functional polymorphism in the serotonin transporter gene and diarrhea predominant irritable bowel syndrome in women. Gut 53:1452–1458
Pata C, Erdal ME, Derici E, Yazar A, Kanik A, Ulu O (2002) Serotonin transporter gene polymorphism in irritable bowel syndrome. Am J Gastroenterol 97:1780–1784
Kim HJ, Camilleri M, Carlson PJ, Cremonini F, Ferber I, Stephens D, Mckinzie S, Zinsmeister AR, Urrutia R (2004) Association of distinct α2 adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders. Gut 53:829–837
Lee DY, Park H, Kim WH, Lee SI, Seo YJ, Choi YC (2004) Serotonin transporter gene polymorphism in healthy adults and patients with irritable bowel syndrome. Korean J Gastroenterol 43:18–22
Camilleri M, Atanasova E, Carlson PJ, Ahmad U, Kim HJ, Viramontes BE, Mckinzie S, Urrutia R (2002) Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome. Gastroenterology 123:425–432
Muller-Lissner SA, Fumagalli I, Bardhan KD, Pace F, Pecherr E, Nault B, Ruegg P (2001) Tegaserod, a 5-HT4 receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Ther 15:1655–1666
Kellow J, Lee OY, Chang FY, Thongsawat S, Mazlam MZ, Yuen H, Gwee KA, Bak YT, Jones J, Wagner A (2003) An Asia-Pacific, double blind, placebo controlled, randomised study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome. Gut 52:671–676
Nyhlin H, Bang C, Elsborg L, Silvennoinen J, Holme I, Ruegg P, Jones J, Wagner A (2004) A double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome. Scand J Gastroenterol 39:119–126
Smeraldi E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M (1998) Polymorphism with the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 3:508–511
Smits KM, Smits LJM, Schouten JSAG, Stelma FF, Nelemans P, Prins MH (2004) Influence of SERTPR and STin2 in the serotonin transporter gene on the effect of selective serotonin reuptake inhibitors in depression: a systematic review. Mol Psychiatry 9:433–441
Muller-Lissner S, Koch G, Talley NJ, Drossman D, Rueegg P, Dunger-Baldauf C, Lefkowitz M (2003) Subject's global assessment of relief: an appropriate method to assess the impact of treatment on irritable bowel syndrome-related symptoms in clinical trials. J Clin Epidemiol 56:310–316
Gelernter J, Cubells JF, Kidd JR, Pakstis AJ, Kidd KK (1999) Population studies of polymorphisms of the Serotonin transporter protein gene. Am J Med Genet (Neuropsychiatr Genet) 88:61–66
Tsai SJ, Ouyang WC, Hong CJ (2002) Association for serotonin transporter gene variable number tandem repeat polymorphism and schizophrenic disorders. Neuropsychobiology 45:131–133
Hoehe MR, Wendel B, Grunewald I, Chiaroni P, Levy N, Morris-Rosendahl D, Macher JP, Sander T, Crocq MA (1998) Serotonin transporter (5-HTT) gene polymorphisms are not associated with susceptibility to mood disorder. Am J Med Genet 81:1–3
Gelernter J, Kranzler H, Cubells JF (1997) Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African and European and Japanese populations and alcohol–dependent subjects. Hum Genet 101:243–246
Kunugi H, Hattori M, Kato T, Tatsumi M, Sakai T, Sasaki T, Hirose T, Nanko S (1997) Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol Psychiatry 2:457–462
You JS, Hu SY, Chen BL, Zhang HG (2005) Serotonin transporter and tryptophan hydroxylase gene polymorphism in Chinese patients with generalized anxiety disorder. Psychiatr Genet 15:7–11
Wang BM, Wang YM, Zhang WM, Zhang QY, Liu WT, Jiang K, Zhang J (2004) Serotonin transporter gene polymorphism in irritable bowel syndrome. Zhonghua Nei Ke Za Zhi 43:439–441 (in Chinese)
Serretti A, Benedetti F, Zanardi R, Smeraldi E (2005) The influence of serotonin transporter promoter polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of antidepressant treatment. Prog Neuropsychopharmacol Biol Psychiatry 29:1074–1084
Liu MT, Rayport S, Jiang Y, Murphy DL, Gershon MD (2002) Expression and function of 5-HT3 receptors in the enteric neurons of mice lacking the serotonin transporter. Am J Physiol Gastrointest 283:G1398–G1411
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Li, Y., Nie, Y., Xie, J. et al. The Association of Serotonin Transporter Genetic Polymorphisms and Irritable Bowel Syndrome and Its Influence on Tegaserod Treatment in Chinese Patients. Dig Dis Sci 52, 2942–2949 (2007). https://doi.org/10.1007/s10620-006-9679-y
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DOI: https://doi.org/10.1007/s10620-006-9679-y