{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T09:27:52Z","timestamp":1740130072028,"version":"3.37.3"},"reference-count":87,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T00:00:00Z","timestamp":1661990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C18281\/A29019"],"award-info":[{"award-number":["C18281\/A29019"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000691","name":"Academy of Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/T002239\/1","MR\/WO14548\/1","MR\/P016065\/1"],"award-info":[{"award-number":["MR\/T002239\/1","MR\/WO14548\/1","MR\/P016065\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,1,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Prolyl hydroxylase (PHD) inhibitors are in clinical development for anaemia in chronic kidney disease. Epidemiological studies have reported conflicting results regarding safety of long-term therapeutic haemoglobin (Hgb) rises through PHD inhibition on risk of cardiovascular disease. Genetic variation in genes encoding PHDs can be used as partial proxies to investigate the potential effects of long-term Hgb rises. We used Mendelian randomization to investigate the effect of long-term Hgb level rises through genetically proxied PHD inhibition on coronary artery disease (CAD: 60 801 cases; 123\u2009504 controls), myocardial infarction (MI: 42 561 cases; 123\u2009504 controls) or stroke (40\u2009585 cases; 406\u2009111 controls). To further characterize long-term effects of Hgb level rises, we performed a phenome-wide association study (PheWAS) in up to 451\u2009099 UK Biobank individuals. Genetically proxied therapeutic PHD inhibition, equivalent to a 1.00\u00a0g\/dl increase in Hgb levels, was not associated (at P\u2009&amp;lt;\u20090.05) with increased odds of CAD; odd ratio (OR) [95% confidence intervals (CI)]\u2009=\u20091.06 (0.84, 1.35), MI [OR (95% CI)\u2009=\u20091.02 (0.79, 1.33)] or stroke [OR (95% CI)\u2009=\u20090.91 (0.66, 1.24)]. PheWAS revealed associations with blood related phenotypes consistent with EGLN\u2019s role, relevant kidney- and liver-related biomarkers like estimated glomerular filtration rate and microalbuminuria, and non-alcoholic fatty liver disease (Bonferroni-adjusted P\u2009&amp;lt;\u20095.42E-05) but these were not clinically meaningful. These findings suggest that long-term alterations in Hgb through PHD inhibition are unlikely to substantially increase cardiovascular disease risk; using large disease genome-wide association study data, we could exclude ORs of 1.35 for cardiovascular risk with a 1.00\u00a0g\/dl increase in Hgb.<\/jats:p>","DOI":"10.1093\/hmg\/ddac215","type":"journal-article","created":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T17:41:15Z","timestamp":1662054075000},"page":"496-505","source":"Crossref","is-referenced-by-count":0,"title":["Genetically proxied therapeutic prolyl-hydroxylase inhibition and cardiovascular risk"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9790-664X","authenticated-orcid":false,"given":"Charli E","family":"Harlow","sequence":"first","affiliation":[{"name":"College of Medicine and Health, University of Exeter , Exeter, Devon EX2 5DW , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vickas V","family":"Patel","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline , Collegeville, PA 19426 , USA"},{"name":"Spark Therapeutics, Inc. , Philadelphia, PA 19104 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawn M","family":"Waterworth","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline , Collegeville, PA 19426 , USA"},{"name":"Immunology Translational Sciences, Janssen , Spring House, PA 19044 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew R","family":"Wood","sequence":"additional","affiliation":[{"name":"College of Medicine and Health, University of Exeter , Exeter, Devon EX2 5DW , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0750-8248","authenticated-orcid":false,"given":"Robin N","family":"Beaumont","sequence":"additional","affiliation":[{"name":"College of Medicine and Health, University of Exeter , Exeter, Devon EX2 5DW , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4966-9170","authenticated-orcid":false,"given":"Katherine S","family":"Ruth","sequence":"additional","affiliation":[{"name":"College of Medicine and Health, University of Exeter , Exeter, Devon EX2 5DW , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9256-6065","authenticated-orcid":false,"given":"Jessica","family":"Tyrrell","sequence":"additional","affiliation":[{"name":"College of Medicine and Health, University of Exeter , Exeter, Devon EX2 5DW , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asami","family":"Oguro-Ando","sequence":"additional","affiliation":[{"name":"College of Medicine and Health, University of Exeter , Exeter, Devon EX2 5DW , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Audrey Y","family":"Chu","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline , Boston, MA 02140 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy M","family":"Frayling","sequence":"additional","affiliation":[{"name":"College of Medicine and Health, University of Exeter , Exeter, Devon EX2 5DW , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,9,1]]},"reference":[{"key":"2023011922194318500_ref1","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1001\/jama.2019.14745","article-title":"Chronic kidney disease diagnosis and management: a review","volume":"322","author":"Chen","year":"2019","journal-title":"JAMA"},{"key":"2023011922194318500_ref2","doi-asserted-by":"crossref","first-page":"A7","DOI":"10.1053\/j.ajkd.2019.01.001","article-title":"US renal data system 2018 annual data report: epidemiology of kidney disease in the United States","volume":"73","author":"Saran","year":"2019","journal-title":"Am. 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