Human Molecular Genetics Advance Access published online on March 28, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn089
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Endocannabinoid receptor 1 gene variations increase risk for obesity and modulate body mass index in European populations
1 CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France 2 Genomic Medicine, Hammersmith Hospital, Imperial College London, U.K 3 Klinik Lindberg, Schickstrasse 11, CH-8400 Winterthur, Switzerland 4 Université Paris Sud, France 5 INSERM U780-IFR69, Villejuif, France 6 Steno Diabetes Center, Niels Steensens Vej 1, NLC2.13, DK-2820 Gentofte, Denmark 7 Faculty of Health Science, University of Aarhus, Aarhus, Denmark
* Address for Correspondence and reprints: Professor Philippe Froguel, Genomic Medicine, Faculty of Medicine, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN, United Kingdom. Tel: + 44 20 8383 3989 Fax: + 44 20 8383 8577 Email: p.froguel{at}imperial.ac.uk
Received January 4, 2008; Revised March 16, 2008; Accepted March 16, 2008
Background: The therapeutic effects of cannabinoid receptor blockade on obesity associated phenotypes underline the importance of the endocannabinoid pathway on the energy balance. Using a staged-approach, we examined the contribution of the endocannabinoid receptor 1 gene (CNR1) on obesity and Body Mass Index in the European population.
Methods: With the input of CNR1 exons and 3' and 5' regions sequencing and HapMap database, we selected and genotyped 26 tag-SNPs in 1,932 obese cases and 1,173 non-obese controls of French European origin. Variants that showed significant associations (P<0.05) with obesity after correction for multiple-testing were further tested in two additional European cohorts including 2,645 individuals. For the identification of the potential causal variant(s), we further genotyped SNPs in high linkage disequilibrium with the obesity-associated variants.
Results: Of twenty five successfully genotyped CNR1 SNPs, 12 showed nominal evidence of association with childhood obesity, class I & II and/or class III adult obesity (1.16<OR<1.40, 0.00003<P<0.04). Intronic SNPs rs806381 and rs2023239, which resisted correction for multiple testing were further associated with higher BMI in both Swiss obese subjects and Danish individuals. The genotyping of all know variants in partial linkage disequilibrium (r2>0.5) with these two SNPs in the initial case-control study, identified two better associated SNPs (rs6454674 and rs10485170).
Conclusions: Our study of 5,750 subjects shows that CNR1 variations increase the risk for obesity and modulate BMI in our European population. As CB1 is a drug target for obesity, a pharmacogenetic analysis of the endocannabinoid blockade obesity treatment may be of interest to identify best responders.
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  A. I. F. Blakemore and P. Froguel Is Obesity Our Genetic Legacy? J. Clin. Endocrinol. Metab., November 1, 2008; 93(11_Supplement_1): s51 - s56. [Abstract] [Full Text] [PDF]
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