TY - JOUR
T1 - Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome
AU - Camilleri, Michael
AU - Atanasova, Elena
AU - Carlson, Paula J.
AU - Ahmad, Umraan
AU - Kim,
AU - Viramontes, Blanca E.
AU - McKinzie, Sanna
AU - Urrutia, Raul
N1 - Funding Information:
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.
PY - 2002/8
Y1 - 2002/8
N2 - 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 prioridefined, 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.
AB - 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 prioridefined, 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.
UR - http://www.scopus.com/inward/record.url?scp=0036325415&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036325415&partnerID=8YFLogxK
U2 - 10.1053/gast.2002.34780
DO - 10.1053/gast.2002.34780
M3 - Article
C2 - 12145795
AN - SCOPUS:0036325415
SN - 0016-5085
VL - 123
SP - 425
EP - 432
JO - Gastroenterology
JF - Gastroenterology
IS - 2
ER -