Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH)

• Published in: International Journal of Obesity Vol. 29; no. 7; pp. 755 - 759
• Main Authors: SIPE, J. C, WAALEN, J, GERBER, A, BEUTLER, E
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 01.07.2005; Nature Publishing Group
• Subjects: Adult; Aged; Amidohydrolases - genetics; Asian Continental Ancestry Group; Back; Biological and medical sciences; Body weight; European Continental Ancestry Group; Fatty acids; Female; Homozygote; Humans; Hybridization; Inactivation; Logistic Models; Male; Medical sciences; Metabolic diseases; Middle Aged; Mutation, Missense; Obesity; Obesity - genetics; Regression analysis; Risk factors; Statistical methods; Obesity; FAAH; Enzymatic activity; Endocannabinoid; Enzyme; Nutrition disorder; Lipids; Hydrolases; Fatty acids; Nutritional status; Polymorphism; Overweight
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/sj.ijo.0802954

The brain endogenous cannabinoid system modulates reward and craving pathways and consequently may affect body weight. A naturally occurring missense polymorphism in the gene encoding fatty acid amide hydrolase (FAAH), the primary enzyme for inactivation of endocannabinoids, is associated with problem drug use. To investigate the relationship between the FAAH cDNA 385 A/A (P129T) polymorphism and overweight disorders in subjects of multiple ethnic backgrounds attending a medical screening clinic. A total of 2667 subjects of white, black and Asian ancestry were genotyped and stratified by a standardized clinic-based assessment of body mass index (BMI, weight in kilograms/(height in meters)(2) or kg/m(2)). Subjects were genotyped for the FAAH cDNA 385 C --> A polymorphism using allele-specific oligonucleotide hybridization methods by investigators blinded to all clinical information. BMI was calculated based on exact clinical measurements and World Health Organization ranges were used to stratify subjects. Statistical methods included the Fisher exact test, Mann-Whitney U-test and multivariable logistic regression analysis. The homozygous FAAH 385 A/A genotype was significantly associated with overweight and obesity in white subjects (P=0.005) and in black subjects (P=0.05) but not in a small group of Asians. The median BMI for all subjects was significantly greater in the FAAH 385 A/A genotype group compared to heterozygote and wild-type groups (P=0.0001). In white subjects, there was an increasing frequency of the FAAH 385 A/A genotype with increasing BMI categories of overweight (P=0.02) and obese (P=0.006) with the same trend in black subjects. These results suggest a role for the FAAH 385 A/A missense polymorphism as an endocannabinoid risk factor in overweight/obesity and may provide indirect evidence to support cannabinoid antagonist treatment strategies in overweight disorders.