Evidence map›Paper›PMID 36055212›Full record

SynthesisAmerican journal of human genetics2022

Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies.

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 and 23 more

Open access · hybridAbstract readMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
2.1field-weighted citation impact, top 11% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed, 13 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

33 authors at 11 institutions in 4 countries.

Charli E HarlowUniversity of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
Josan GandawijayaUniversity of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
Rosemary A BamfordUniversity of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
Emily-Rose MartinUniversity of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
Andrew R WoodUniversity of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
Peter J van der MostUniversity of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen 9713, the Netherlands.
Toshiko TanakaLongitudinal Studies Section, Translation Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
Hampton L LeonardLaboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA; Data Tecnica International, Glen Echo, MD 20812, USA; Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD 20892, USA.
Amy S EtheridgeEshelman School of Pharmacy and Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
Federico InnocentiAbbVie Inc., 1000 Gateway Boulevard, South San Francisco, CA 94080, USA.
Robin N BeaumontUniversity of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
Jessica TyrrellUniversity of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
Mike A NallsLaboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA; Data Tecnica International, Glen Echo, MD 20812, USA; Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD 20892, USA.
Eleanor M SimonsickLongitudinal Studies Section, Translation Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
Pranav S GarimellaDivision of Nephrology-Hypertension, University of California San Diego, San Diego, CA, USA.
Eric J ShiromaLaboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD 20892, USA.
Niek VerweijUniversity of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen 9713, the Netherlands.
Peter van der MeerUniversity of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen 9713, the Netherlands.
Ron T GansevoortUniversity of Groningen, University Medical Center Groningen, Department of Nephrology, Groningen 9713, the Netherlands.
Harold SniederUniversity of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen 9713, the Netherlands.
Paul J GallinsBioinformatics Research Center, North Carolina State University, 1 Lampe Drive, Raleigh, NC 27695, USA.
Dereje D JimaBioinformatics Research Center, North Carolina State University, 1 Lampe Drive, Raleigh, NC 27695, USA; Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27606, USA.
Fred WrightBioinformatics Research Center, North Carolina State University, 1 Lampe Drive, Raleigh, NC 27695, USA.
Yi-Hui ZhouBioinformatics Research Center, North Carolina State University, 1 Lampe Drive, Raleigh, NC 27695, USA.
Luigi FerrucciLongitudinal Studies Section, Translation Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
Stefania BandinelliGeriatric Unit, Azienda Sanitaria Firenze, Florence 50134, Italy.
Dena G HernandezLaboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
Pim van der HarstDepartment of Cardiology, University Medical Center Utrecht, Utrecht 3584, the Netherlands.
Vickas V PatelGlaxoSmithKline, Collegeville, PA 19426, USA.
Dawn M WaterworthGlaxoSmithKline, Collegeville, PA 19426, USA.
Audrey Y ChuGlaxoSmithKline, Boston, MA 02140, USA.
Asami Oguro-AndoUniversity of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK. Electronic address: a.oguro-ando@exeter.ac.uk.
Timothy M FraylingUniversity of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK. Electronic address: t.m.frayling@exeter.ac.uk.
University of Exeter · GBNational Institute on Aging · USUniversity Medical Center Groningen · NLNorth Carolina State University · USGlaxoSmithKline (United States) · USNational Institutes of Health · USAbbVie (United States) · USAzienda Sanitaria di Firenze · ITUniversity Medical Center Utrecht · NLUniversity of California San Diego · USUniversity of North Carolina at Chapel Hill · US

Funding

Translational Research Support CoreP30ES025128 · NORTH CAROLINA STATE UNIVERSITY RALEIGH · 2025 to 2025
$1.5M
Biotechnology and Biological Sciences Research Council BB/K003240/1Medical Research Council MC_PC_17228Medical Research Council MC_QA137853Medical Research Council MR/M008924/1Medical Research Council MR/T002239/1Medical Research Council MR/WO14548/1NIEHS NIH HHS P30 ES025128NIMHD NIH HHS R01 MD009164NINR NIH HHS R01 NR012459Wellcome TrustWellcome Trust WT097835MFWellcome Trust WT101650MA
6 · The paper itself

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.

Indexed as

AnemiaCoronary Artery DiseaseMyocardial InfarctionRenal Insufficiency, ChronicGenome-Wide Association StudyHumansMendelian Randomization Analysisanaemia in chronic kidney diseasecardiovascular disease riskCRISPR-Cas9drug-target mendelian randomizationfunctional genomicsfunctional validationgene editinggenome-wide association studymendelian randomizationpopulation studiesstatistical genetics

Identifiers

PMID36055212
PMCPMC9502050
OpenAlexW4294012503

What Socratic holds

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LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.