Cannabinoid Receptor 1 Gene and Irritable Bowel Syndrome: 8 Phenotype and Quantitative Traits

250 words) 41 Genetic variations in metabolism of endocannabinoids and in CNR1 (gene for cannabinoid 1 42 receptor) are associated with symptom phenotype, colonic transit, and left colon motility in 43 irritable bowel syndrome (IBS). Our aim was to evaluate associations between two variations in 44 CNR1 genotype (rs806378 and [AAT]n triplets) with symptom phenotype, small bowel and 45 colonic transit, and rectal sensations in 455 patients with IBS and 228 healthy controls. Small 46 bowel and colonic transit were measured by scintigraphy; rectal sensation by isobaric 47 distensions. Associations with genotype were assessed by χ test (symptom phenotype) and 48 ANCOVA (quantitative traits) based on a dominant genetic model. Significant association of 49 CNR1 rs806378 (but not CNR1 [AAT]n) genotype and symptom phenotype was observed (χ 50 p=0.028). There was significant association of CNR1 rs806378 (p=0.014; CC vs CT/TT) with 51 colonic transit in IBS-diarrhea (IBS-D) group; the TT group had fastest colonic transit at 24 and 52 48h. There was significant overall association of CNR1 rs806378 with sensation rating of gas 53 (p=0.025), but not pain; strongest associations for gas ratings were in IBS-D (p=0.002) and IBS54 alternating (p=0.025) subgroups. For CNR1 (AAT)n, gene by phenotype interactions were 55 observed for colonic transit at 24 (p=0.06) and 48h (p=0.002) and gas (p=0.046, highest for IBS56 D, p=0.034), but not pain sensation; the strongest association with transit was in controls, not in 57 IBS. These data support the hypothesis that cannabinoid receptors may play a role in control of 58 colonic transit and sensation in humans and deserve further study as potential mediators or 59 therapeutic targets in lower FGID. 60