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

Feng, QiPing; Vickers, KC; Anderson, MP; Levin, Michael G.; Chen, W; Harrison, D. G.; Wilke, RA

doi:10.1038/ncomms2973

Cited by 14 publications

(10 citation statements)

References 42 publications

(46 reference statements)

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“…The rs806371 polymorphism in the CNR1 promoter is a common functional variant associated with high-density lipoprotein cholesterol levels (Feng et al, 2013). Using 1% of 100,000 BioVU subject records claiming European Ancestry for further study (50% female and 50% male subjects), as well as functional assays, this polymorphism was found to alter HDL-C level in humans by generating a novel regulatory DNA-binding site capable of reducing CNR1 expression.…”

Section: Natural Polymorphisms and Alternative Splice Variantsmentioning

confidence: 99%

CB 1 and CB 2 Receptor Pharmacology

Howlett

Abood

2017

Advances in Pharmacology

255

219

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The CB1 and CB2 cannabinoid receptors (CB1R, CB2R) are members of the G protein coupled receptor (GPCR) family that were identified over 20 years ago. CB1Rs and CB2Rs mediate the effects of Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive constituent of marijuana and subsequently identified endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonoyl glycerol. CB1Rs and CB2Rs have both similarities and differences in their pharmacology. Both receptors recognize multiple classes of agonist and antagonist compounds and produce an array of distinct downstream effects. Natural polymorphisms and alternative splice variants may also contribute to their pharmacological diversity. As our knowledge of the distinct differences grows, we may be able to target select receptor conformations and their corresponding pharmacological responses. This chapter will discuss their pharmacological characterization, distribution, phylogeny and signaling pathways. In addition, the effects of extended agonist exposure and how that affects signaling and expression patterns of the receptors is considered.

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Section: Natural Polymorphisms and Alternative Splice Variantsmentioning

confidence: 99%

CB 1 and CB 2 Receptor Pharmacology

Howlett

Abood

2017

Advances in Pharmacology

255

219

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“…Critical for genetic studies, reporter assays can be used to estimate the effect of genetic variants on regulatory activity by comparing the activity of different alleles of the same regulatory element. For those reasons, reporter assays have been valuable for identifying individual regulatory variants that contribute to phenotype Feng et al 2013;Fogarty et al 2014;Stadhouders et al 2014;Guo et al 2015).…”

Section: High-throughput Measurement Of Regulatory Element Activitymentioning

confidence: 99%

Genomic approaches for understanding the genetics of complex disease

Lowe

Reddy

2015

Genome Res.

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There are thousands of known associations between genetic variants and complex human phenotypes, and the rate of novel discoveries is rapidly increasing. Translating those associations into knowledge of disease mechanisms remains a fundamental challenge because the associated variants are overwhelmingly in noncoding regions of the genome where we have few guiding principles to predict their function. Intersecting the compendium of identified genetic associations with maps of regulatory activity across the human genome has revealed that phenotype-associated variants are highly enriched in candidate regulatory elements. Allele-specific analyses of gene regulation can further prioritize variants that likely have a functional effect on disease mechanisms; and emerging high-throughput assays to quantify the activity of candidate regulatory elements are a promising next step in that direction. Together, these technologies have created the ability to systematically and empirically test hypotheses about the function of noncoding variants and haplotypes at the scale needed for comprehensive and systematic follow-up of genetic association studies. Major coordinated efforts to quantify regulatory mechanisms across genetically diverse populations in increasingly realistic cell models would be highly beneficial to realize that potential.

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“…That limitation motivates the development of complementary empirical approaches to assay the consequences of noncoding genetic variation on regulatory element activity (Feng et al 2013;Fogarty et al 2014;Stadhouders et al 2014;Guo et al 2015). In a reporter gene expression assay, for example, a gene regulatory element is cloned into a plasmid, where the element can control the expression of a fluorescent or chemiluminescent protein.…”

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confidence: 99%

Massively parallel quantification of the regulatory effects of noncoding genetic variation in a human cohort

et al. 2015

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We report a novel high-throughput method to empirically quantify individual-specific regulatory element activity at the population scale. The approach combines targeted DNA capture with a high-throughput reporter gene expression assay. As demonstration, we measured the activity of more than 100 putative regulatory elements from 95 individuals in a single experiment. In agreement with previous reports, we found that most genetic variants have weak effects on distal regulatory element activity. Because haplotypes are typically maintained within but not between assayed regulatory elements, the approach can be used to identify causal regulatory haplotypes that likely contribute to human phenotypes. Finally, we demonstrate the utility of the method to functionally fine map causal regulatory variants in regions of high linkage disequilibrium identified by expression quantitative trait loci (eQTL) analyses.

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

Cited by 14 publications

References 42 publications

CB 1 and CB 2 Receptor Pharmacology

CB 1 and CB 2 Receptor Pharmacology

Genomic approaches for understanding the genetics of complex disease

Massively parallel quantification of the regulatory effects of noncoding genetic variation in a human cohort

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