Pharmacogenetics of low dose clonidine in irritable bowel syndrome

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Abstract
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: α2A (C‐1291G), α2C (Del 322‐325), GNβ3 (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 (P = 0.024). There were significant associations between post‐CLO responses and gene variations for ΔGV (α2A and SLC6A4), rectal sensation of gas (α2A, GNβ3), urgency (α2A); and pain (GNβ3 and SLC6A4); and rectal compliance (SLC6A4). α2A, GNβ3 and SLC6A4 genotypes significantly modify responses to CLO on sensory and motor GI functions in health and IBS.