| Application: | 7140, CCL3L1 and CCR5 delta 32 CNV study in extremes of the lung function distribution in smokers |
| Title: | Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function |
| Size: | 3.9 MB |
| Archived: | 12 Jul 2018 |
| Stability: | Complete |
| Personal: | Contains individual-level data |
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Notes
Background: The CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. Small molecule CCR5 antagonists exist, including the approved antiretroviral drug maraviroc, and therapeutic monoclonal antibodies are in development. Repositioning of drugs and targets into new disease areas can accelerate the availability of new therapies and substantially reduce costs. As it has been shown that drug targets with genetic evidence supporting their involvement in the disease are more likely to be successful in clinical development, using genetic association studies to identify new target repurposing opportunities could be fruitful. Here we investigate the potential of perturbation of the CCL3L1-CCR5 axis as treatment for respiratory disease. Europeans typically carry between 0 and 5 copies of CCL3L1 and this multi-allelic variation is not detected by widely used genome-wide single nucleotide polymorphism studies. Methods: We directly measured the complex structural variation of CCL3L1 using the Paralogue Ratio Test and imputed (with validation) CCR5d32 genotypes in 5,000 individuals from UK Biobank, selected from the extremes of the lung function distribution, and analysed DNA and RNAseq data for CCL3L1 from the 1000 Genomes Project. Results: We confirmed the gene dosage effect of CCL3L1 copy number on CCL3L1 mRNA expression levels. We found no evidence for association of CCL3L1 copy number or CCR5d32 genotype with lung function. Conclusions: These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.Application 7140
CCL3L1 and CCR5 delta 32 CNV study in extremes of the lung function distribution in smokers
COPD is a long-term progressive condition affecting ~900,000 people in the UK accounting for ~30,000 deaths and over £500m of NHS costs annually. Copy number variation (CNV) could account for some of the variability in COPD risk and lung function. We aim to study CNV of two genes in relation to COPD and lung function. CCL3L1 encodes a pro-inflammatory cytokine. There is a relationship between CCL3L1 copy number (CN) and protein expression levels, and some evidence that CCL3L1 CN is associated with lung function. CCR5 encodes a receptor for CCL3L1 and contains a polymorphic 32bp deletion. Genetic approaches to understanding the mechanisms underlying COPD aim to discover targets for drug development and unravel disease heterogeneity facilitating stratified approaches to treatment. CCL3L1 and CCR5d32 CN measurements for all UK Biobank particpants included in this project will be returned to UK Biobank to be made available to other researchers. CN at some regions can be inferred from SNP data but complex CN regions (where CN varies from 0 to 6 or more) require custom-designed assays. CCL3L1 CN varies from 1 to 6 and the ?gold standard? approach for measurement is the paralogue ratio test (PRT). CCL3L1 is a ligand for CCR5, a receptor that contains a polymorphic deletion associated with other diseases, including asthma. We will genotype CCL3L1 CN and CCR5d32 in smokers with good or bad lung function and test for association with lung function to clarify the therapeutic opportunities of the CCL3L1-CCR5 axis in COPD. We will genotype 2500 heavy smokers with good lung function and 2500 heavy smokers with poor lung function. These will be selected from the 50,000 individuals for whom DNA has been extracted for the UK BiLEVE consortium.
| Lead investigator: | Dr Edward Hollox |
| Lead institution: | University of Leicester |
1 Publication
| Pub ID | Title | Author(s) | Year | Journal |
|---|---|---|---|---|
| 1492 | Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function | Adewoye AB et al. | 2018 | Wellcome Open Res |
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