Variants at the Endocannabinoid Receptor CB1 Gene (CNR1) and Insulin Sensitivity, Type 2 Diabetes, and Coronary Heart Disease
Variants at the Endocannabinoid Receptor CB1 Gene (CNR1) and Insulin Sensitivity, Type 2 Diabetes, and Coronary Heart Disease
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DOI：
10.1038/oby.2011.135
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发表时间：
2011-10-01
期刊：
影响因子：
6.9
通讯作者：
Meigs, James B.
中科院分区：
文献类型：
--
作者：
de Miguel-Yanes, Jose M.;Manning, Alisa K.;Meigs, James B.
抑制内源性大麻素受体CB1可改善胰岛素敏感性，降低血糖，减缓动脉粥样硬化。我们分析了编码CB1基因CNR1的常见变异是否与胰岛素抵抗、2型糖尿病（T2D）或冠心病（CHD）的风险相关。我们研究了Framingham Offspring Study的2411名参与者（平均年龄60岁，52%为女性）的数量性状和冠心病，以及Framingham SHARe数据库的T2D风险。我们对19个单核苷酸多态性（snp）进行了基因分型，这些snp标记了85% （at r(2) = 0.8）的常见（>5%）CNR1 snp。收集第7次（1999-2001）空腹血糖和胰岛素。我们使用年龄、性别、bmi调整模型来检验基因型与胰岛素抵抗（HOMA(IR)）（线性混合效应模型）、T2D或冠心病的稳态模型评估的附加关联。为了解释snp的多次测试，我们生成了经验P值。SNP位点rs806365的C等位基因（频率为57.4%）与CNR1的4.1 kb 3'相似，与HOMA(IR) （n = 2261, β = 0.05 / C，经验P = 0.01）、T2D（674例，比值比= 1.19 / C，标称P = 0.01）和冠心病（237例，危险比= 1.23 / C，标称P = 0.04）的增加相关。rs806365与HOMA（IR）的关联在两个独立队列(National Health and Nutrition Examination Survey III遗传队列（NHANES-III）加partner病例对照糖尿病研究；2,540名白人，β = 0.037，名义P = 0.007)，但在葡萄糖和胰岛素相关性状联盟（MAGIC）联盟的大型meta分析中没有（n = 29,248，名义P = 0.74）。在糖尿病遗传学复制和荟萃分析中，rs806365与T2D （n = 10,128，标称P = 0.31）或PROCARDIS中与冠心病（n = 13,614，标称P = 0.37）的关联均未被证实。虽然初步结果支持，但我们发现CNR1的常见变异与胰岛素抵抗、T2D或冠心病之间没有可重复的统计关联。
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%), similar to 4.1 kb 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, 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, beta = 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.