Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies
Year: 2022
Type: review
Study design: Observational Study
Abstract: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.
Authors: Charli E. Harlow, Josan Gandawijaya, Rosemary A. Bamford, Emily-Rose Martin, Andrew R. Wood, Peter J. van der Most, Toshiko Tanaka, Hampton L. Leonard, Amy S. Etheridge, Federico Innocenti, Robin N. Beaumont, Jessica Tyrrell, Mike A. Nalls, Eleanor M. Simonsick, Pranav S. Garimella, Eric J. Shiroma, Niek Verweij, Peter van der Meer, Ron T. Gansevoort, Harold Snieder, Paul J. Gallins, Dereje D. Jima, Fred Wright, Yi-hui Zhou, Luigi Ferrucci, Stefania Bandinelli, Dena G. Hernandez, Pim van der Harst, Vickas V. Patel, Dawn M. Waterworth, Audrey Y. Chu, Asami Oguro-Ando, Timothy M. Frayling
Institutions: University of Exeter, Royal Devon & Exeter NHS Foundation Trust, University Medical Center Groningen, University of Groningen, National Institute on Aging, National Institutes of Health, Data Tecnica International (United States), University of North Carolina at Chapel Hill, AbbVie (United States), University of California San Diego, North Carolina State University, Azienda Sanitaria di Firenze, University Medical Center Utrecht, GlaxoSmithKline (United States)
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: GlaxoSmithKline, Roche, Wellcome Trust, Academy of Medical Sciences, Ministero della Salute, National Institutes of Health, Medical Research Council, Biotechnology and Biological Sciences Research Council, National Institute on Aging, National Institute of Nursing Research, National Institute of Environmental Health Sciences, National Institute on Minority Health and Health Disparities
Awards: G100949702, Using genetics to test the disease consequences of higher adiposity uncoupled from its adverse metabolic effects, The role of common genetic variants for predicting the modulation of Cardio vascular outcomes by daprodustat, G1909691036, G2372998584, G2863306651, G3389114139, G4559153192, G5850737185, Engineering Synthetic Microbial Communities for Biomethane Production, End of Life in the Very Old, G670738241, G6889598148, G6924604795, G7283484021, G7959818251, Accelerated discovery of functional non-coding genomic variation using single molecule real-time (SMRT) sequencing., G8608864222, G861947890, HISPANIC SECONDARY STROKE PREVENTION INITIATIVE, G88327988, G8995606975, Center for Human Health and the Environment (CHHE)
OpenAlex ID: W4294012503