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

Wellcome Open Research

article

Adeolu B. Adewoye¹  Nick Shrine²  Linda Odenthal-Hesse¹  Samantha Welsh³  Anders Malarstig⁴  Scott Jelinsky⁴  Iain Kilty⁴  Martin D. Tobin²  Edward J. Hollox¹  Louise V. Wain² 

[1] Department of Genetics and Genome Biology, University of Leicester;Department of Health Sciences, University of Leicester;UK Biobank;Pfizer Worldwide Research and Development;National Institute of Health Research Biomedical Research Centre, University of Leicester

关键词: copy number variation;    lung function;    CCL3L1;    CCR5;    CNV;    UK Biobank;   

DOI  :  10.12688/wellcomeopenres.13902.2

学科分类：内科医学

来源: Wellcome

【 摘 要 】

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 ofCCL3L1 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 ofCCL3L1 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 forCCL3L1 from the 1000 Genomes Project.Results: We confirmed the gene dosage effect ofCCL3L1 copy number onCCL3L1 mRNA expression levels.  We found no evidence for association ofCCL3L1 copy number orCCR5d32 genotype with lung function.Conclusions: These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.

【 授权许可】

CC BY