Pharmacogenetics of low dose clonidine in irritable bowel syndrome

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: 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.

Figure 1

Changes in satiation test and gastric volume measurements before and after treatment with clonidine (0.1 or 0.15 mg doses) in study participants.

Figure 2

Interaction of α2A with change (PP-fasting) in gastric volume (p=0.016) post-clonidine treatment with opposite patterns by genotype observed in health versus IBS.

Figure 3

Interaction of SLC6A4 genotypes with satiation volumes (p=0.063) and change in gastric volume (p=0.046) post-clonidine treatment with opposite patterns by genotype observed in health versus IBS.

Figure 4

Interactions of genotype by disease group (IBS vs. health) for post-clonidine treatment rectal sensation ratings Upper panel - Interaction effect for α2A by disease group detected for gas (p=0.053) and urgency (p=0.026), but not pain. Middle panel - Interactions were observed between GNβ3 genotype and disease group for gas (p=0.049) and pain (p=0.022) and, to a lesser extent, urgency (p=0.068). Lower panel - Association of disease group (health vs. IBS) with pain sensation, p=0.009, but not for gas and urgency scores.

Figure 5

Interaction of SLC6A4 genotype by disease group for post-treatment rectal compliance: a significant SLC6A4 genotype by disease group interaction for rectal compliance (p=0.03) was detected. Thus, rectal compliance was lower (Pr_1/2 higher) in IBS patients who had the LL SLC6A4 genotype, in contrast to effect of genotype in healthy controls.