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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)  CCR5 d32 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  CCR5 d32 genotype with lung function.    Conclusions:  These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.

Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function