Context: The endocannabinoid system modulates food intake and body weight in animal models. Treatment with the cannabinoid type 1 receptor (CB1) blocker, rimonabant, reduces body weight in obese individuals.

Objective: To determine whether single nucleotide polymorphims (SNPs) of the gene encoding CB1, CNR1, are associated with body fat mass and distribution in two independent samples of white European adult men.

Design, Setting, and Participants: The 3813A/G and 4895A/G SNPs at the exon 4 of CNR1 were genotyped in 930 participants to the Olivetti Prospective Heart Study (OPHS) in southern Italy and in 216 participants to the Wandsworth Heart & Stroke Study (WHSS) in England. Retrospective analysis was also performed on a OPHS sub-sample (n = 360) for which anthropometric data from 1987 and 1994-1995 examinations were available.

Main Outcome Measures: CNR1 genotypes and anthropometric measures of body fat distribution.

Results: In the OPHS study, the 3813G allele was associated with increased subscapular skinfold thickness (SS) (24.2 ± 9.1 mm vs 22.8 ± 7.7 mm, P = 0.031) and waist circumference (WC) (99.1 ± 8.8 cm vs 97.7 ± 8.8 cm, P = 0.050). No association was observed with 4895A/G variant. Haplotype analysis confirmed that the unique haplotype carrying the 3813G was associated with increased WC and SS. Similar results were observed in the OPHS retrospective sub-sample and in the WHSS sample. In the latter, the 3813G was associated with increased WC (96.8 ± 11.3 vs 91.6 ± 10.4, P = 0.006).

Conclusion: Genetic variants at CNR1 are associated with obesity-related phenotypes in men. The detection of polymorphic variants in genes involved in the process of fat accumulation may help identify specific targets for pharmacological treatment of obesity and related metabolic abnormalities.