Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
Nat Commun. 2013;4:1973. doi: 10.1038/ncomms2973.
Type 1 cannabinoid receptor blockers increase high-density lipoprotein cholesterol levels. Although genetic variation in the type 1 cannabinoid receptor--encoded by the CNR1 gene--is known to influence high-density lipoprotein cholesterol level as well, human studies conducted to date have been limited to genetic markers such as haplotype-tagging single nucleotide polymorphisms. Here we identify rs806371 in the CNR1 promoter as the causal variant. We re-sequence the CNR1 gene and genotype all variants in a DNA biobank linked to comprehensive electronic medical records. By testing each variant for association with high-density lipoprotein cholesterol level in a clinical practice-based setting, we localize a putative functional allele to a 100-bp window in the 5'-flanking region. Assessment of variants in this window for functional impact on electrophoretic mobility shift assay identifies rs806371 as a novel regulatory binding element. Reporter gene assays confirm that rs806371 reduces gene expression, thereby linking CNR1 gene variation to high-density lipoprotein cholesterol level in humans.
1 型大麻素受体阻滞剂可增加高密度脂蛋白胆固醇水平。虽然已知 1 型大麻素受体（由 CNR1 基因编码）的遗传变异也会影响高密度脂蛋白胆固醇水平，但迄今为止进行的人类研究仅限于遗传标记，如单核苷酸多态性的单体型标记。在这里，我们确定 CNR1 启动子中的 rs806371 是因果变异。我们重新测序了 CNR1 基因，并对与综合电子病历相关的 DNA 生物库中的所有变体进行了基因分型。通过在基于临床实践的环境中测试每个变体与高密度脂蛋白胆固醇水平的关联，我们将一个假定的功能等位基因定位到 5'侧翼区域的 100bp 窗口。评估该窗口中对电泳迁移率变动分析的功能影响的变体，确定 rs806371 是一个新的调节结合元件。报告基因检测证实 rs806371 降低了基因表达，从而将 CNR1 基因变异与人类的高密度脂蛋白胆固醇水平联系起来。
