title: A common functional promoter variant links CNR1 gene expression to HDL cholesterol level.
abstract: 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.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. QiPing.Feng@vanderbilt.edu
authors.forename: Q
authors.initials: Q
authors.lastname: Feng
authors.forename: K C
authors.initials: KC
authors.lastname: Vickers
authors.forename: M P
authors.initials: MP
authors.lastname: Anderson
authors.forename: M G
authors.initials: MG
authors.lastname: Levin
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: D G
authors.initials: DG
authors.lastname: Harrison
authors.forename: R A
authors.initials: RA
authors.lastname: Wilke
mesh_terms: D008076:Cholesterol, HDL / Q000097:blood*; D002877:Chromosomes, Human / Q000235:genetics; D015331:Cohort Studies; D004247:DNA / Q000378:metabolism; D003710:Demography; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: C571130:CNR1 protein, human; D008076:Cholesterol, HDL; D043884:Receptor, Cannabinoid, CB1; D004247:DNA