| Title: | Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies |
| Journal: | American Journal of Human Genetics |
| Published: | 1 Sep 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36055212/ |
| DOI: | https://doi.org/10.1016/j.ajhg.2022.08.004 |
| URL: | http://www.cell.com/article/S0002929722003561/pdf |
| Citations: | 6 (4 in last 2 years) as of 8 Aug 2024 |
Publication 12248
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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.</p>
33 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
1 Application
| Application ID | Title |
|---|---|
| 9072 | The Genetics of anthropometric traits ? Height, weight, BMI and waist circumference |
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