Pharmacogenetics of low dose clonidine in irritable bowel syndrome.
Adrenergic and serotonergic (ADR-SER) mechanisms alter gut (gastrointestinal, GI) sensorimotor functions. We aimed to determine whether candidate ADR-SER genes affect GI responses to low dose clonidine (CLO) in humans. Forty healthy and 120 irritable bowel syndrome (IBS) participants received CLO, 0.1 mg or 0.15 mg b.i.d., for 6 days. At baseline and post-CLO, we measured: gastric volume (GV); satiation volume; rectal compliance, sensation thresholds and ratings with distensions. Genetic variations tested were: alpha2A (C-1291G), alpha2C (Del 322-325), GNbeta3 (C825T) and solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4) (serotonin transporter linked polymorphic region). CLO reduced volume to satiation (P = 0.002), postprandial GV (P < 0.001), sensation threshold for pain (<0.001); CLO increased rectal compliance (P = 0.024). There were significant associations between post-CLO responses and gene variations for DeltaGV (alpha2A and SLC6A4), rectal sensation of gas (alpha2A, GNbeta3), urgency (alpha2A); and pain (GNbeta3 and SLC6A4); and rectal compliance (SLC6A4). alpha2A, GNbeta3 and SLC6A4 genotypes significantly modify responses to CLO on sensory and motor GI functions in health and IBS.
Camilleri
M
M
Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, MN 55905, USA. camilleri.michael@mayo.edu
Busciglio
I
I
Carlson
P
P
McKinzie
S
S
Burton
D
D
Baxter
K
K
Ryks
M
M
Zinsmeister
A R
AR
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage*; D003000:Clonidine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics
D000316:Adrenergic alpha-Agonists; C454420:G-protein beta3 subunit; D018341:Receptors, Adrenergic, alpha-2; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D020962:Heterotrimeric GTP-Binding Proteins; D003000:Clonidine