Gastroenterology

Gastroenterology

Volume 123, Issue 2, August 2002, Pages 425-432
Gastroenterology

Clinical–Alimentary Tract
Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome,☆☆

https://doi.org/10.1053/gast.2002.34780Get rights and content

Abstract

Background & Aims: A serotonin (5-HT)3 receptor antagonist relieves symptoms in women with diarrhea-predominant irritable bowel syndrome (D-IBS). 5-HT undergoes reuptake by a transporter protein (SERT). Polymorphisms in the promoter for synthesis of SERT (SERT-P) influence response to serotonergic medications in depression. Our hypothesis is that polymorphisms of the promoter region for the SERT influence colonic transit in response to treatment with alosetron in D-IBS. Methods: Thirty patients (15 men, 15 women) with D-IBS received 1 mg twice a day alosetron for 6 weeks; colonic transit was measured by scintigraphy at baseline and at the end of treatment. Twenty-three patients consented to provide blood DNA samples. Long, short, and heterozygous SERT polymorphisms were identified by polymerase chain reaction–based restriction fragment length polymorphisms and confirmed by direct sequencing. We sought pharmacogenomic association of long, short, and heterozygote polymorphisms with a change in colonic transit and with an a priori–defined, clinically meaningful change in transit at 24 hours (>1.1 colonic regions). Results: SERT polymorphisms tended to be associated with colonic transit response (P = 0.075); there was a greater response in those with long homozygous than heterozygous polymorphisms (P = 0.039). Slowing of transit by >1.1 colonic region was observed in 9 women and 3 men and was more frequent in long homozygous than heterozygous patients (P = 0.024). Age, gender, and duration of IBS were not significantly different in the 3 groups. Conclusions: Genetic polymorphisms at the SERT promoter influence response to a 5-HT3 antagonist in D-IBS and may influence benefit-risk ratio with this class of compounds.

GASTROENTEROLOGY 2002;123:425-432

Section snippets

Patient population and timing of physiological studies

Thirty European American patients with IBS associated with diarrhea and fulfilling Rome I criteria25 were included in this study. Gastrointestinal and colonic transit measurements were performed during the baseline period and during the last week of a 6-week trial with alosetron 1 mg twice a day. Detailed results of the transit measurements and adverse effects during the pharmacodynamic trial are published elsewhere.15 The sample size of 30 patients was selected based on an anticipated change

Patients and duration of IBS

Demographic data of the 30 white participants, 15 women and 15 men, are as follows: mean age 43.2 ± 3 years (women, 46 ± 4 years; men, 40 ± 4 years); mean duration of IBS 11.2 ± 2.0 years (women, 9.2 ± 2.3 years; men, 13.1 ± 3.2 years).

Effect of alosetron on colonic transit

The colonic geometric center at 24 hours was significantly lower (suggesting slower overall colonic transit) following treatment with alosetron compared with baseline.15 The change in overall colonic transit was significantly greater in women compared with men

Discussion

Our study demonstrates for the first time that the homozygous long polymorphism of the SERT-P is associated with a greater biological response and the likelihood of a clinically meaningful effect of alosetron, compared with the response in heterozygotes. These data are consistent with the study by Lesch et al.23 in human lymphoblasts expressing the 3 common genotypes at this locus, “ll,” “ls,” and “ss,” and the observation that there was higher serotonin transport and higher messenger RNA

References (57)

  • T Stivland et al.

    Scintigraphic measurement of regional gut transit in idiopathic constipation

    Gastroenterology

    (1991)
  • M Vassallo et al.

    Transit through the proximal colon influences stool weight in the irritable bowel syndrome

    Gastroenterology

    (1992)
  • CJ Steadman et al.

    Selective 5-hydroxytryptamine type 3 receptor antagonism with ondansetron as treatment for diarrhea-predominant irritable bowel syndrome: a pilot study

    Mayo Clin Proc

    (1992)
  • DH Silverman et al.

    Regional cerebral activity in normal and pathological perception of visceral pain

    Gastroenterology

    (1997)
  • BG Pollock et al.

    Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression

    Neuropsychopharmacology

    (2000)
  • MR Heath et al.

    Alosetron does not improve anxiety in female IBS patients

    Gastroenterology

    (2000)
  • S Caras et al.

    Cilansetron shows efficacy in male and female non-constipated patients with irritable bowel syndrome in a United States study

    Gastroenterology

    (2001)
  • M Camilleri et al.

    Irritable bowel syndrome

    Aliment Pharmacol Ther

    (1997)
  • PA Cann et al.

    Irritable bowel syndrome: relationship of disorders in the transit of a single solid meal to symptom patterns

    Gut

    (1983)
  • MR von der Ohe et al.

    Serotonergic mediation of postprandial colonic tonic and phasic responses in humans

    Gut

    (1994)
  • G Ragnarsson et al.

    Pain is temporarily related to eating but not to defecation in irritable bowel syndrome (IBS). Patients' descriptions of diarrhea, constipation, and symptom variation during a prospective 6-week study

    Eur J Gastroenterol Hepatol

    (1998)
  • M-G Choi et al.

    A pilot study of motility and tone of the left colon in diarrhea due to functional disorders and dysautonomia

    Am J Gastroenterol

    (1997)
  • M Camilleri et al.

    A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea predominant irritable bowel syndrome

    Arch Intern Med

    (2001)
  • M Camilleri et al.

    Improvement in pain and bowel function in female irritable bowel syndrome patients with alosetron, a 5HT3-receptor antagonist

    Aliment Pharmacol Ther

    (1999)
  • WE Evans et al.

    Pharmacogenomics: translating functional genomics into rational therapeutics

    Science

    (1999)
  • JN. Weinstein

    Pharmacogenomics: teaching old drugs new tricks

    N Engl J Med

    (2000)
  • HL McLeod et al.

    Pharmacogenomics: unlocking the human genome for better drug therapy

    Annu Rev Pharmacol Toxicol

    (2001)
  • JR Shannon et al.

    Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency

    N Engl J Med

    (2000)
  • Cited by (0)

    Address requests for reprints to: Michael Camilleri, M.D., Mayo Clinic, Charlton 7-154, 200 First Street S.W., Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 255-5720.

    ☆☆

    Supported in part by General Clinical Research Center grant RR00585, grants R01 DK54681 and K24 DK02638 (to M.C.), and grants RO1 DK52913 and DK56220 (to R.U.) from the National Institutes of Health. The transit measurements in this study were supported by a grant from Glaxo Wellcome.

    View full text