Bioinformatics identifies genes responsible for varying patient responses to COPD treatment
Fios Genomics has collaborated with Reprocell (Biopta) on their study: Application of pharmacogenomics and bioinformatics to exemplify the utility of human ex vivo organoculture models in the field of precision medicine. The project involved bioinformatics analysis of microRNA (miRNA) expression data, genotype information and their association with experimental outcomes.
Large-scale genomic and transcriptomic data were generated from living human lung tissue samples extracted from patients diagnosed with chronic obstructive pulmonary disease (COPD). Fios used transcriptomic, genomic and statistical analysis approaches to explain inter-patient drug efficacy variation in this dataset. These approaches were also combined with newly developed pharmacological tissue culture technologies.
Generating The Data
COPD patient tissues were ethically acquired from 25 patients. Tissue specimens were stimulated ex-vivo with several ‘standard of care’ COPD therapeutics. Then, TNF-alpha inhibition was applied post-treatment as an indirect, primary estimate of drug response. Portions of the biopsied tissue were examined by specialist collaborating companies, such as Sistemic and Stratified Medicines Scotland Innovation Centre. These collaborators generated the microRNA (miRNA) expression and whole exome sequencing (WES) data that were analysed by Fios Genomics.
Analysing The Data
Fios applied bioinformatics analysis techniques across all the data generated to provide an integrative approach to the multiple information sources. Our bioinformaticians analysed TNF-alpha inhibition as a measure of drug response first. Then they combined this with the miRNA profiling data and targeted exome sequencing data.
Our team began with a quality control evaluation of the 25 biopsy samples and the TNF-alpha inhibition results to understand how patients respond differently to the drug treatments. It became apparent that patient response was bimodal (See figure 1, below) with patient-specific responses observed.
Fios bioinformaticians were able to link patient response to genotypic information and miRNA expression data from those same patients. Consequently, we discovered associations of genotype at two particular genes, SMAD3 and CYP2E1, with TNF-alpha inhibition hence patient response. (See Figure 2 below.)
For example, at the rs2249695 single nucleotide polymorphism located within an intron of CYP2E1, the T allele correlated with greater TNF-alpha inhibition. Similar observations had previously been reported in the literature in different patient cohorts and in different demographics (Yang et al., 2010, Exp. Biol. Med.), suggestive of a relationship between patient genotype and COPD patient response to drug treatment.
The functions of these two COPD-treatment associated genes are diverse. SMAD3 is involved in the propagation of immune system signalling within cells. CYP2E1, however, is part of the cytochrome P450 family of proteins which are involved in the metabolism of drugs by the liver. The association of drug metabolism and immune signalling with COPD drug treatment outcome presents two distinct opportunities. Firstly, to develop new therapeutics and enhance the efficacy of COPD drugs, and secondly to provide a method of stratifying those patients who will and will not respond to these drug treatments.
Watch The Webinar
Fios Genomics’ Technical Director, Dr Max Bylesjö, discussed these findings further in the webinar: Application of pharmacogenomics and bioinformatics to exemplify the utility of human ex vivo organoculture models in the field of precision medicine, which you can view on-demand here.
Fios regularly provides bioinformatics analysis of genomic data for precision medicine projects. To learn more about the full range of services we provide please visit our bioinformatics services page. Our experts would be happy to talk you through any projects you have in mind or answer any questions you may have, so don’t hesitate to contact us.
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