Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome.
OBJECTIVE
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-HT(3) antagonist in D-IBS and may influence benefit-risk ratio with this class of compounds.
Camilleri
Michael
M
Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Mayo Foundation, Rochester, Minnesota 55905, USA. camilleri.michael@mayo.edu
Atanasova
Elena
E
Carlson
Paula J
PJ
Ahmad
Umraan
U
Kim
H Jae
HJ
Viramontes
Blanca E
BE
McKinzie
Sanna
S
Urrutia
Raul
R
D000328:Adult; D002243:Carbolines / Q000494:pharmacology / Q000627:therapeutic use; D002352:Carrier Proteins / Q000235:genetics*; D003106:Colon / Q000187:drug effects / Q000502:physiology; D003109:Colonic Diseases, Functional / Q000188:drug therapy / Q000235:genetics*; D003967:Diarrhea / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins
D002243:Carbolines; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C090840:alosetron; D012701:Serotonin