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Cited by 13Erythropoietin and Anemia TreatmentGenetic Associations and EpidemiologyGenetics and Physical Performance

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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Harlow, Charli E., Gandawijaya, Josan, Bamford, Rosemary A., Martin, Emily-Rose, Wood, Andrew R., van der Most, Peter J., Tanaka, Toshiko, Leonard, Hampton L. +25 more·2022·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2022.08.004PMC PMC9502050
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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.

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  • PTVs in EPOR were associated with increased erythropoietin (ptv model; P = 3.5 × 10−24; β = 1.78; 95% CI, 1.43 to 2.12).

    “For example, PTVs in EPOR, encoding the erythropoietin receptor, were associated with increased erythropoietin, an example of compensatory upregulation (‘ptv’ model; P = 3.5 × 10−24; β = 1.78; 95% confidence interval (CI), 1.43 to 2.12)28.”

    From Rare variant associations with plasma protein levels in the UK Biobank (2023) · cites this paper as [28]

    The Results (Table 1; page unavailable) report an association between a cis-EPO variant and circulating EPO levels, not an analysis of protein-truncating variants in EPOR. Searches of our copy for EPOR, protein-truncating variants, compensatory upregulation, and the stated P value found no passage reporting the claimed association or statistics. (LLM, conf=0.76)

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Authors
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.
Affiliations
  • University of Exeter (GB)
  • National Institute on Aging (US)
  • National Institutes of Health (US)
  • University of North Carolina at Chapel Hill (US)
  • AbbVie (United States) (US)
  • University of California San Diego (US)
  • University Medical Center Groningen (NL)
  • North Carolina State University (US)
  • Azienda Sanitaria di Firenze (IT)
  • GlaxoSmithKline (United States) (US)
Corresponding author
Frayling, Timothy M.
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2022-09
Volume
109
Issue
9
Pages
1638-1652
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2022.08.004
PMC
PMC9502050
OpenAlex
W4294012503
Cited by
13
References
7
Citations by year
2025: 5 · 2024: 2 · 2023: 4 · 2022: 2
FWCI
0.58
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion, public-domain)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
  • UNC Libraries
Funders
  • BBSRC (BB/K003240/1)
  • National Institutes of Health (P30ESO25128)
  • Wellcome Trust (WT101650MA, WT097835MF)
  • GlaxoSmithKline
  • Academy of Medical Sciences
  • Medical Research Council (MR/P016065/1, MR/M008924/1, MR/WO14548/1, MR/T002239/1)
  • Roche
  • National Institute on Aging (N01-AG-6-2106, N01-AG-6-2101, N01-AG-6-2103, R01-AG028050 2)
  • National Institute of Nursing Research (R01-NR012459, ICS110.1/RF97.71)
  • Ministero della Salute (9072)
Topics
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
Keywords
erythropoietin, HIF prolyl hydroxylase inhibitors, anemia of chronic kidney disease, cardiovascular safety, coronary artery disease, myocardial infarction, stroke, Mendelian randomization
MeSH terms
Anemia, Coronary Artery Disease, Humans, Myocardial Infarction, Renal Insufficiency, Chronic, Genome-Wide Association Study, Mendelian Randomization Analysis

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