Abstract
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) CCR5del32 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 CCR5del32 genotype with lung function. Conclusions: These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.
Highlights
Genome-wide association studies have identified thousands of disease-gene associations leading to new disease insight and potential new approaches to treatment
Our study provides robust large-scale confirmation of a gene dosage effect of CCL3L1 copy number on CCL3L1 mRNA levels, and emphasises the strong dependence of CCL3L1:CCL3 mRNA ratio on copy number, with CCL3L1 copy number accounting for 50% of total variation
It is clear that CCL3L1 is expressed at much lower levels than CCL3, the MIP-1alpha isoform encoded by CCL3L1 (LD78beta) has a much stronger affinity to the CCR5 receptor than MIP-1alpha isoform CCL3 (LD78alpha)
Summary
Genome-wide association studies have identified thousands of disease-gene associations leading to new disease insight and potential new approaches to treatment. The MIP-1alpha (encoded by CCL3 and CCL3L1)-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. The MIP-1alpha (encoded by CCL3 and CCL3L1)-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses2 It is perturbed by CCR5 antagonists such as Pfizer’s maraviroc, the only CCR5 antagonist to be approved by the United States Food and Drug Administration. The CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. 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. We found no evidence for association of version 2 (revision)
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