Benzinou M, Chevre JC, Ward KJ, Lecoeur C, Dina C, Lobbens S et al. Endocannabinoid receptor 1 gene variations increase risk for obesity and modulate body mass index in European populations. Hum Mol Genet 17: 1916-1921

CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
Human Molecular Genetics (Impact Factor: 6.39). 08/2008; 17(13):1916-21. DOI: 10.1093/hmg/ddn089
Source: PubMed


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 (BMI) in the European population. With the input of CNR1 exons and 3' and 5' regions sequencing and HapMap database, we selected and genotyped 26 tagging single-nucleotide polymorphisms (SNPs) in 1932 obese cases and 1173 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 2645 individuals. For the identification of the potential causal variant(s), we further genotyped SNPs in high linkage disequilibrium (LD) with the obesity-associated variants. Of the 25 successfully genotyped CNR1 SNPs, 12 showed nominal evidence of association with childhood obesity, class I and 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 LD (r(2) > 0.5) with these two SNPs in the initial case-control study, identified two better associated SNPs (rs6454674 and rs10485170). Our study of 5750 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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    • "In addition, the rs2501431 and rs1049353 polymorphisms have been linked to depression (Monteleone et al., 2010; Mitjans et al., 2013) and the latter has also been associated with antidepressant response (Mitjans et al., 2013). CNR1 is also a candidate gene for metabolic disorders such as obesity, hypercholesterolemia and insulin resistance (Benzinou et al., 2008; Feng et al., 2010). For example, the minor alleles of rs1535255 and rs2023239 were associated with lower risk of metabolic syndrome in schizophrenia (Yu et al., 2013). "
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    ABSTRACT: Cannabinoid receptor 1 (CNR1) gene polymorphisms have been associated with central and peripheral effects of cannabis and schizophrenia pathophysiology. Here, we have tested whether three CNR1 variants (rs1049353, rs1535255 and rs2023239) are associated with changes in brain volumes, body mass index (BMI) or psychopathological scores in a 3-year longitudinal study of 65 first-episode psychosis patients. The rs1049353 at-risk allele was significantly associated with a greater reduction of caudate volume, and the rs2023239 T/C polymorphism showed a significant decrease in thalamic volume after the 3-year period. For those who were not cannabis users, the rs1535255 and rs2023239 polymorphisms had effects in lateral ventricle (LV), and LV and white matter, respectively. The rs2023239 variant also was associated with significant improvements in positive and negative symptoms of schizophrenia. There was no significant effect of any of the variants on changes in BMI over the 3-year study. Finally, an interaction between all three polymorphisms was found involving evolution of positive symptoms. These findings suggest that the cannabinoid pathway is associated with schizophrenia evolution over time. However, further studies using larger cohorts are needed to confirm these results. If confirmed, the present findings could lead in subsequent investigations for identification of novel drug targets for improved treatment of patients suffering from schizophrenia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · May 2015 · Psychiatry Research: Neuroimaging
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    • "In our study we found no association of rs1049353 with NAFLD in either controls or PCOS women. In the study of Benzinou et al. rs806381 was associated with obesity and BMI [55]. According to one study, it was also associated with TG level but not with BMI or WHR [56]. "
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    ABSTRACT: Context. Polycystic ovary syndrome (PCOS) is frequently associated with nonalcoholic fatty liver disease (NAFLD). The endocannabinoid system may play a crucial role in the pathogenesis of NAFLD. Polymorphism of the cannabinoid receptor 1 gene (CNR1) may be responsible for individual susceptibility to obesity and related conditions. Objective. To determine the role of genetic variants of CNR1 in the etiopathology of NAFLD in women with PCOS. Design and Setting. Our department (a tertiary referral center) conducted a cross-sectional, case-controlled study. Subjects. 173 women with PCOS (aged 20-35) and 125 healthy, age- and weight-matched controls were studied. Methods. Hepatic steatosis was assessed by ultrasound evaluation. Single nucleotide polymorphisms of CNR1 (rs806368, rs12720071, rs1049353, rs806381, rs10485170, rs6454674) were genotyped. Results. Frequency of the G allele of rs806381 (P < 0.025) and the GG genotype of rs10485170 (P < 0.03) was significantly higher in women with PCOS and NAFLD than in PCOS women without NAFLD. Frequency of the TT genotype of rs6454674 was higher in PCOS women with NAFLD (not significantly, P = 0.059). In multivariate stepwise regression, allele G of rs806381 was associated with PCOS + NAFLD phenotype. Conclusion. Our preliminary results suggest the potential role of CNR1 polymorphisms in the etiology of NAFLD, especially in PCOS women.
    Full-text · Article · Jul 2014 · International Journal of Endocrinology
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    • "For example, adiponectin, a hormone that plays a key role in regulation of glucose and fatty acids75 and has reduced levels in obesity and type 2 diabetes,76 has been found to be genetically associated with these diseases around the world.77–81 In addition, association studies of various nominated candidate genes have also implicated the genes encoding such factors as the cannabinoid receptor 1 (CNR1), dopamine receptor 2 (DRD2), serotonin receptor 2C (HTR2C), and SLC6A4,82–86 but the most replicated of them is the Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma(PPARγ) gene, which has been extensively associated with both obesity87 and type 2 diabetes.88 These studies support the conclusion that obesity is a complex disease influenced by many genes with small effect size; thus there is a great need for nonhypothesis genome wide approaches. "
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    ABSTRACT: It has long been known that there is a genetic component to obesity, and that characterizing this underlying factor would likely offer the possibility of better intervention in the future. Monogenic obesity has proved to be relatively straightforward, with a combination of linkage analysis and mouse models facilitating the identification of multiple genes. In contrast, genome-wide association studies have successfully revealed a variety of genetic loci associated with the more common form of obesity, allowing for very strong consensus on the underlying genetic architecture of the phenotype for the first time. Although a number of significant findings have been made, it appears that very little of the apparent heritability of body mass index has actually been explained to date. New approaches for data analyses and advances in technology will be required to uncover the elusive missing heritability, and to aid in the identification of the key causative genetic underpinnings of obesity.
    Full-text · Article · Jan 2013 · Annals of the New York Academy of Sciences
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