A common functional promoter variant links CNR1 gene expression to HDL cholesterol level

CB(1) receptor blockers increase HDL-C levels. Although genetic variation in the CB(1) receptor – encoded by the CNR1 gene – is known to influence HDL-C level as well, human studies conducted to date have been limited to genetic markers such as haplotype tagging SNPs. Here we identify rs806371 in the CNR1 promoter as the causal variant. We resequenced the CNR1 gene and genotype all variants in a DNA biobank linked to comprehensive electronic medical records. By testing each variant for association with HDL-C level in a clinical practice-based setting, we localize a putative functional allele to a 100bp window in the 5′-flanking region. Assessment of variants in this window for functional impact on electrophoretic mobility shift assay identified rs806371 as a novel regulatory binding element. Reporter gene assays confirm that rs806371 reduces HDL-C gene expression, thereby linking CNR1 gene variation to HDL-C level in humans.