Academic Journal
Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies
| العنوان: | Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies |
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| المؤلفون: | Harlow, C. E., Gandawijaya, J., Bamford, R. A., Martin, E. R., Wood, A. R., van der Most, P. J., Tanaka, T., Leonard, H. L., Etheridge, A. S., Innocenti, F., Beaumont, R. N., Tyrrell, J., Nalls, M. A., Simonsick, E. M., Garimella, P. S., Shiroma, E. J., Verweij, N., van der Meer, P., Gansevoort, R. T., Snieder, H., Gallins, P. J., Jima, D. D., Wright, F., Zhou, Y. H., Ferrucci, L., Bandinelli, S., Hernandez, D. G., van der Harst, P., Patel, V. V., Waterworth, D. M., Chu, A. Y., Oguro-Ando, A., Frayling, T. M. |
| بيانات النشر: | Cell Press |
| سنة النشر: | 2022 |
| المجموعة: | RD&E Research Repository (Royal Devon and Exeter NHS Foundation Trust) |
| مصطلحات موضوعية: | Anemia/drug therapy/genetics, Coronary Artery Disease/genetics, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Myocardial Infarction/genetics, Renal Insufficiency, Chronic/genetics, CRISPR-Cas9, anaemia in chronic kidney disease, cardiovascular disease risk, drug-target mendelian randomization, functional genomics, functional validation, gene editing, mendelian randomization, population studies, statistical genetics |
| الوصف: | 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. ; The article is available via Open Access. Click on the 'Additional link' above to access the full-text. ; Published version, accepted version (6 month embargo), submitted version |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 36055212 |
| Relation: | https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(22)00356-1; Am J Hum Genet. 2022 Sep 1;109(9):1638-1652. doi:10.1016/j.ajhg.2022.08.004.; https://rde.dspace-express.com/handle/11287/622619; American journal of human genetics |
| DOI: | 10.1016/j.ajhg.2022.08.004 |
| الاتاحة: | https://doi.org/10.1016/j.ajhg.2022.08.004 https://rde.dspace-express.com/handle/11287/622619 |
| Rights: | Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved. ; http://creativecommons.org/publicdomain/zero/1.0/ |
| رقم الانضمام: | edsbas.CD32219C |
| قاعدة البيانات: | BASE |
| تدمد: | 36055212 |
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| DOI: | 10.1016/j.ajhg.2022.08.004 |