1. Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function
- Author
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Linda Odenthal-Hesse, Nick Shrine, Martin D. Tobin, Anders Mälarstig, Iain Kilty, Scott A. Jelinsky, Louise V. Wain, Edward J. Hollox, Samantha Welsh, and Adeolu B. Adewoye
- Subjects
0301 basic medicine ,UK Biobank ,CNV ,Medicine (miscellaneous) ,Single-nucleotide polymorphism ,CCL3L1 ,Biology ,Bioinformatics ,Gene dosage ,General Biochemistry, Genetics and Molecular Biology ,Structural variation ,03 medical and health sciences ,0302 clinical medicine ,Genotype ,Copy-number variation ,1000 Genomes Project ,030304 developmental biology ,Genetic association ,0303 health sciences ,copy number variation ,lung function ,Articles ,3. Good health ,030104 developmental biology ,030220 oncology & carcinogenesis ,CCR5 ,030217 neurology & neurosurgery ,Research Article - 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) 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.
- Published
- 2018