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Variants at the Endocannabinoid Receptor CB1 Gene ( CNR1 ) and Insulin Sensitivity, Type 2 Diabetes, and Coronary Heart Disease
Author(s) -
MiguelYanes Jose M.,
Manning Alisa K.,
Shrader Peter,
McAteer Jarred B.,
Goel Anuj,
Hamsten Anders,
Fox Caroline S.,
Florez Jose C.,
Dupuis Josée,
Meigs James B.
Publication year - 2011
Publication title -
obesity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.438
H-Index - 199
eISSN - 1930-739X
pISSN - 1930-7381
DOI - 10.1038/oby.2011.135
Subject(s) - type 2 diabetes , insulin resistance , medicine , single nucleotide polymorphism , framingham heart study , framingham risk score , diabetes mellitus , hazard ratio , endocrinology , odds ratio , cohort , genotype , insulin , disease , biology , genetics , confidence interval , gene
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.