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 if 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 r2=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 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%), ~4.1kb 3′ from CNR1, was associated with increased HOMA-IR (n=2,261, beta=0.05 per C, empirical P=0.01), risk of T2D (674 cases, OR=1.19 per C, nominal P=0.01) and CHD (237 cases, HR=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 (NHANES III plus Partners Case-Control Diabetes Study; 2,540 white individuals, beta=0.037, nominal P=0.007), but not in the large MAGIC Consortium (n=29,248, nominal P=0.74). The association of rs806365 was not replicated either with T2D in 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.