Written by:
VP and Head of Centre for Genomics Research, Discovery Sciences, R&D, AstraZeneca
Associate Principal Scientist, Discovery Sciences, R&D, AstraZeneca
Results from the largest proteogenomics study to date could transform how we, and others, approach drug discovery. After analysing over 50,000 human exomes from the UK Biobank, we uncovered links between rare protein-coding genetic variants and nearly 3,000 plasma proteins. The findings, which we are making available to the global scientific community at AZPheWAS.com, are uncovering previously unknown insights into disease biology that can help accelerate the identification of new therapeutic targets and biomarkers.
As said by co-author of our recent Nature study and Executive Vice President, BioPharmaceuticals R&D (retiring), Mene Pangalos: “A selective high-quality molecule will never become a medicine if it is modulating the wrong target.” That’s why selecting the right target remains the most important decision we make in the drug discovery process.
Drug candidates that target genes or proteins that are clearly linked to human disease are much more likely to demonstrate clinically meaningful outcomes and therefore, are more likely to be approved to benefit patients. Proteins are the functional unit of biology, providing crucial roles in structure, regulation, energy regulation and more. Because of their important roles throughout the body, mutations or variations in genes that affect protein function or levels of expression can greatly affect biological processes and human health.
Delving deeper: Combining genomics with proteomics to advance drug discovery
In a breakthrough study conducted by our Centre for Genomic Research (CGR) research team, we analysed over 50,000 human exomes in the UK Biobank dataset to uncover the contribution of rare protein-coding genetic variants on nearly 3,000 plasma proteins.1 Plasma proteins circulate in the blood, originating from multiple organs and cell types. Therefore, they can provide a unique snapshot of the current state of health or disease.
Several previous studies have shown thousands of associations between common or non-protein coding genetic variants and plasma protein abundance, however, the effect of rare protein-coding variants on plasma proteins has not been studied at this scale, until now.
Compared with common genetic variants, rare variants offer stronger evidence and unique insights into the direct relationships between genes, proteins, and their roles in disease. By focusing on these variants, we identified over 4,400 significant ‘protein quantitative trait loci’ – gene variants associated with protein function essential to health. Over three-quarters of these places had never been detected, even in previous studies that used a similar UK Biobank cohort.2
The findings from this research allow us to better understand the impact that certain genes and proteins have on disease. Now, we can apply these insights to drug discovery and development, providing novel insights into disease mechanisms, possible off-target drug effects, novel target discovery, and more.
For example, using this analysis, we discovered previously undescribed plasma biomarkers associated with a rare variant in the HSD17B13 gene that is implicated in protection against chronic liver diseases including non-alcoholic steatohepatitis (NASH).1 Having a better understanding of the biological effects of this variant could allow us to better develop targeted precision medicine therapeutics to improve outcomes for people with NASH.
This finding, along with the thousands of others that exist within this dataset have the potential to be transformational to how we, along with the broader scientific community, approach drug discovery. Ultimately, by improving target identification, we can move towards matching patients with the treatments that are most likely to help.
Opening our science to the world through collaboration
Open science, the commitment to sharing scientific information, is fundamental to the progress of scientific research. That’s why we have made all summary statistics from this research available on AZPheWAS.com for use by academics and researchers across the globe. Once on the website, researchers can search by gene, variant or phenotype to discover genetically anchored disease-protein associations to gain novel insights and a deeper understanding of the biology of common diseases.
Our main purpose is to push the boundaries of science to deliver life-changing medicines. We know that we can’t do this alone, so we have established an open and collaborative way of working to promote greater research efficiency while reducing unnecessary duplication in genomics research.
