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

Q. Feng (), K.C. Vickers, M.P. Anderson, M.G. Levin, W. Chen, D.G. Harrison and R.A. Wilke
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Q. Feng: Vanderbilt University School of Medicine
K.C. Vickers: Vanderbilt University School of Medicine
M.P. Anderson: National Heart, Lung and Blood Institute, National Institutes of Health
M.G. Levin: National Heart, Lung and Blood Institute, National Institutes of Health
W. Chen: Vanderbilt University School of Medicine
D.G. Harrison: Vanderbilt University School of Medicine
R.A. Wilke: Vanderbilt University School of Medicine

Nature Communications, 2013, vol. 4, issue 1, 1-7

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2973

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