Genetic variation in endocannabinoid metabolism, gastrointestinal motility, and sensation.
Cannabinoid agonist inhibits gastrointestinal motility. The endocannabinoid, anandamide, is inactivated by fatty acid amide hydrolase (FAAH). A single nucleotide polymorphism in the human FAAH gene (C385A) reduces FAAH expression. Our aim was to evaluate associations between FAAH genotype variation and symptom phenotype, gastric emptying and volume, colonic transit, and rectal sensation in patients with functional gastrointestinal disorders (FGID). 482 FGID patients [Rome II positive, 159 constipation disorders, 184 diarrhea disorders (D-IBS), 86 mixed bowel function (M-IBS), 20 chronic abdominal pain (CAP), 33 functional dyspepsia], and 252 healthy volunteers (HV) underwent questionnaires and studies of phenotype and genotype from 2000 to 2007: 250 gastric emptying, 210 fasting and postprandial gastric volume, 152 colonic transit, and 123 rectal sensation. All had FAAH genotype [CC vs. polymorphic (CA/AA)] determined by TaqMan. FAAH genotype distribution of FGID patients and HV did not deviate from Hardy-Weinberg equilibrium. There was a significant association of FAAH genotype with FGID phenotype (overall chi(2), P = 0.011) and with specific individual phenotypes (P = 0.048). Thus FAAH CA/AA increases the odds (relative to HV) for D-IBS (P = 0.008), M-IBS (P = 0.012), and, possibly, CAP (P = 0.055). There was a significant association of FAAH CA/AA genotype with accelerated colonic transit in D-IBS (P = 0.037). There was no association of FAAH genotype with rectal sensation thresholds or ratings. The association of genetic variation in metabolism of endocannabinoids with symptom phenotype in D-IBS and M-IBS and with faster colonic transit in D-IBS supports the hypothesis that cannabinoid mechanisms may play a role in the control of colonic motility in humans and deserve further study.
Camilleri
Michael
M
Mayo Clinic, Rochester, MN 55905, USA. camilleri.michael@mayo.edu
Carlson
Paula
P
McKinzie
Sanna
S
Grudell
April
A
Busciglio
Irene
I
Burton
Duane
D
Baxter
Kari
K
Ryks
Michael
M
Zinsmeister
Alan R
AR
D000328:Adult; D000581:Amidohydrolases / Q000235:genetics*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D063388:Endocannabinoids; D005260:Female; D005746:Gastric Emptying / Q000235:genetics; D005767:Gastrointestinal Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000235:genetics*; D005772:Gastrointestinal Transit / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D012007:Rectum / Q000503:physiopathology*; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D012677:Sensation / Q000235:genetics*; D012684:Sensory Thresholds; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D000099252:Fatty Acid Amide Hydrolases