title: Variants at the endocannabinoid receptor CB1 gene (CNR1) and insulin sensitivity, type 2 diabetes, and coronary heart disease.
abstract: Inhibition of the endocannabinoid receptor CB1 improves insulin sensitivity, lowers glycemia, and slows atherosclerosis. We analyzed whether common variants in the gene encoding CB1, CNR1, are associated with insulin resistance, risk of type 2 diabetes (T2D) or coronary heart disease (CHD). We studied 2,411 participants of the Framingham Offspring Study (mean age 60 years, 52% women) for quantitative traits and CHD, and the Framingham SHARe database for T2D risk. We genotyped 19 single-nucleotide polymorphisms (SNPs) that tagged 85% (at r(2) = 0.8) of common (>5%) CNR1 SNPs. Fasting blood glucose and insulin at the 7th (1999-2001) exam were collected. We used age-, sex-, BMI-adjusted models to test additive associations of genotype with homeostasis model assessment of insulin resistance (HOMA(IR)) (linear mixed-effect models), T2D, or CHD. To account for multiple tests of SNPs, we generated empirical P values. The C allele at SNP rs806365 (frequency, 57.4%), ~4.1 kb 3' from CNR1, was associated with increased HOMA(IR) (n = 2,261, β = 0.05 per C, empirical P = 0.01), risk of T2D (674 cases, odds ratio = 1.19 per C, nominal P = 0.01) and CHD (237 cases, hazard ratio = 1.23 per C, nominal P = 0.04). The association of rs806365 with HOMA(IR) was replicated in a meta-analysis of two independent cohorts (National Health and Nutrition Examination Survey III genetic cohort (NHANES-III) plus Partners Case-Control Diabetes Study; 2,540 white individuals, β = 0.037, nominal P = 0.007), but not in the large Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) Consortium (n = 29,248, nominal P = 0.74). The association of rs806365 was not replicated either with T2D in Diabetes Genetics Replication and Meta-analysis (DIAGRAM) (n = 10,128, nominal P = 0.31), or with CHD in PROCARDIS (n = 13,614, nominal P = 0.37). Although supported by initial results, we found no reproducible statistical association of common variation at CNR1 with insulin resistance, T2D, or CHD.
authors.affiliation: General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: de Miguel-Yanes
authors.forename: Alisa K
authors.initials: AK
authors.lastname: Manning
authors.forename: Peter
authors.initials: P
authors.lastname: Shrader
authors.forename: Jarred B
authors.initials: JB
authors.lastname: McAteer
authors.forename: Anuj
authors.initials: A
authors.lastname: Goel
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
mesh_terms: D000368:Aged; D000483:Alleles; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009749:Nutrition Surveys; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D040641:Quantitative Trait Loci; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics*; D012307:Risk Factors
chemical_list: D001786:Blood Glucose; D007328:Insulin; D043884:Receptor, Cannabinoid, CB1