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Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies.
Harlow, Charli E; Gandawijaya, Josan; Bamford, Rosemary A; Martin, Emily-Rose; Wood, Andrew R; van der Most, Peter J; Tanaka, Toshiko; Leonard, Hampton L; Etheridge, Amy S; Innocenti, Federico; Beaumont, Robin N; Tyrrell, Jessica; Nalls, Mike A; Simonsick, Eleanor M; Garimella, Pranav S; Shiroma, Eric J; Verweij, Niek; van der Meer, Peter; Gansevoort, Ron T; Snieder, Harold; Gallins, Paul J; Jima, Dereje D; Wright, Fred; Zhou, Yi-Hui; Ferrucci, Luigi; Bandinelli, Stefania; Hernandez, Dena G; van der Harst, Pim; Patel, Vickas V; Waterworth, Dawn M; Chu, Audrey Y; Oguro-Ando, Asami; Frayling, Timothy M.
Affiliation
  • Harlow CE; University of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
  • Gandawijaya J; University of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
  • Bamford RA; University of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
  • Martin ER; University of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
  • Wood AR; University of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
  • van der Most PJ; University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen 9713, the Netherlands.
  • Tanaka T; Longitudinal Studies Section, Translation Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
  • Leonard HL; Laboratory 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.
  • Etheridge AS; Eshelman 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.
  • Innocenti F; AbbVie Inc., 1000 Gateway Boulevard, South San Francisco, CA 94080, USA.
  • Beaumont RN; University of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
  • Tyrrell J; University of Exeter Medical School, University of Exeter, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
  • Nalls MA; Laboratory 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.
  • Simonsick EM; Longitudinal Studies Section, Translation Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
  • Garimella PS; Division of Nephrology-Hypertension, University of California San Diego, San Diego, CA, USA.
  • Shiroma EJ; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD 20892, USA.
  • Verweij N; University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen 9713, the Netherlands.
  • van der Meer P; University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen 9713, the Netherlands.
  • Gansevoort RT; University of Groningen, University Medical Center Groningen, Department of Nephrology, Groningen 9713, the Netherlands.
  • Snieder H; University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen 9713, the Netherlands.
  • Gallins PJ; Bioinformatics Research Center, North Carolina State University, 1 Lampe Drive, Raleigh, NC 27695, USA.
  • Jima DD; Bioinformatics 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.
  • Wright F; Bioinformatics Research Center, North Carolina State University, 1 Lampe Drive, Raleigh, NC 27695, USA.
  • Zhou YH; Bioinformatics Research Center, North Carolina State University, 1 Lampe Drive, Raleigh, NC 27695, USA.
  • Ferrucci L; Longitudinal Studies Section, Translation Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
  • Bandinelli S; Geriatric Unit, Azienda Sanitaria Firenze, Florence 50134, Italy.
  • Hernandez DG; Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
  • van der Harst P; Department of Cardiology, University Medical Center Utrecht, Utrecht 3584, the Netherlands.
  • Patel VV; GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Waterworth DM; GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Chu AY; GlaxoSmithKline, Boston, MA 02140, USA.
  • Oguro-Ando A; University 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.
  • Frayling TM; University 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.
Am J Hum Genet ; 109(9): 1638-1652, 2022 09 01.
Article in En | MEDLINE | ID: mdl-36055212
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Coronary Artery Disease / Renal Insufficiency, Chronic / Anemia / Myocardial Infarction Type of study: Clinical_trials / Diagnostic_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limits: Humans Language: En Journal: Am J Hum Genet Year: 2022 Document type: Article Affiliation country: United kingdom
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Coronary Artery Disease / Renal Insufficiency, Chronic / Anemia / Myocardial Infarction Type of study: Clinical_trials / Diagnostic_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limits: Humans Language: En Journal: Am J Hum Genet Year: 2022 Document type: Article Affiliation country: United kingdom