Sarah Collier
Last active: 4/7/2017

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

Feng Q, Vickers KC, Anderson MP, Levin MG, Chen W, Harrison DG, Wilke RA
Nat Commun. 2013 4: 1973

PMID: 23748922 · PMCID: PMC3873874 · 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.

MeSH Terms (18)

Cholesterol, HDL Chromosomes, Human Cohort Studies Demography DNA Electrophoretic Mobility Shift Assay Gene Expression Regulation Genes, Reporter Haplotypes Homozygote Humans Middle Aged Molecular Sequence Data Polymorphism, Single Nucleotide Promoter Regions, Genetic Protein Binding Receptor, Cannabinoid, CB1 Sequence Analysis, DNA

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