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: alpha 2A (C-1291G), alpha 2C (Del 322-325), GN beta 3 (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 Delta GV (alpha 2A and SLC6A4), rectal sensation of gas (alpha 2A, GN beta 3), urgency (alpha 2A); and pain (GN beta 3 and SLC6A4); and rectal compliance (SLC6A4). alpha 2A, GN beta 3 and SLC6A4 genotypes significantly modify responses to CLO on sensory and motor GI functions in health and IBS.