{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T15:38:34Z","timestamp":1782488314709,"version":"3.54.5"},"reference-count":21,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":503,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100012569","name":"University of Toledo","doi-asserted-by":"publisher","award":["Deans Postdoctoral to Faculty Fellowship"],"award-info":[{"award-number":["Deans Postdoctoral to Faculty Fellowship"]}],"id":[{"id":"10.13039\/100012569","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL143082"],"award-info":[{"award-number":["HL143082"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Red blood cell distribution width (RDW) is a measurement of the variation in size and volume of red blood cells (RBCs). Increased RDW, indicating a high heterogeneity of RBCs, is prominently associated with a variety of illnesses, especially cardiovascular diseases. However, the significance of this association to the onset and progression of cardiovascular and renal diseases is unknown. We hypothesized that a genetic predisposition for increased RDW is an early risk factor for cardiovascular and renal comorbidities. Since there is no known animal model of increased RDW, we examined a CRISPR\/Cas9 gene-edited rat model (RfflTD) which presented with features of hematologic abnormalities as well as severe cardiac and renal comorbidities. A mass-spectrometry based quantitative proteomic analysis indicated anemia of these rats presented with significant downregulation of hemoglobin and haptoglobin. Decreased hemoglobin and increased RDW were further observed in RfflTD through complete blood count. Next, a systematic temporal assessment detected an early increased RDW in RfflTD, which was prior to the development of other comorbidities. The primary mutation of RfflTD is a 50bp deletion in a non-coding region, whereby, our study has serendipitously identified this locus as a novel quantitative trait locus (QTL) for RDW. To our knowledge, our study is the first to experimentally pinpoint a QTL for RDW and provides a novel genetic rat model mimicking the clinical association of increased RDW with poor cardio-renal outcomes.<\/jats:p>","DOI":"10.1242\/dmm.044081","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T17:39:21Z","timestamp":1585762761000},"source":"Crossref","is-referenced-by-count":8,"title":["Genetic predisposition for increased red blood cell distribution width is an early risk factor for cardiovascular and renal comorbidities"],"prefix":"10.1242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0838-5094","authenticated-orcid":false,"given":"Xi","family":"Cheng","sequence":"first","affiliation":[{"name":"Center for Hypertension and Precision Medicine, Program in Physiological Genomics, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blair","family":"Mell","sequence":"additional","affiliation":[{"name":"Center for Hypertension and Precision Medicine, Program in Physiological Genomics, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Alimadadi","sequence":"additional","affiliation":[{"name":"Center for Hypertension and Precision Medicine, Program in Physiological Genomics, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Galla","sequence":"additional","affiliation":[{"name":"Center for Hypertension and Precision Medicine, Program in Physiological Genomics, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron G.","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Center for Hypertension and Precision Medicine, Program in Physiological Genomics, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saroj","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Center for Hypertension and Precision Medicine, Program in Physiological Genomics, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkatesha","family":"Basrur","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bina","family":"Joe","sequence":"additional","affiliation":[{"name":"Center for Hypertension and Precision Medicine, Program in Physiological Genomics, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,1,1]]},"reference":[{"key":"2021042700245761200_DMM044081C1","doi-asserted-by":"publisher","first-page":"e902","DOI":"10.7759\/cureus.902","article-title":"Importance of mean red cell distribution width in hypertensive patients","volume":"8","author":"Bilal","year":"2016","journal-title":"Cureus"},{"key":"2021042700245761200_DMM044081C2","doi-asserted-by":"publisher","first-page":"A86","DOI":"10.1016\/0735-1097(93)90468-G","article-title":"Atrial natriuretic peptide in heart failure","volume":"22","author":"Brandt","year":"1993","journal-title":"J. Am. Coll. Cardiol."},{"key":"2021042700245761200_DMM044081C3","doi-asserted-by":"publisher","first-page":"D1005","DOI":"10.1093\/nar\/gky1120","article-title":"The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019","volume":"47","author":"Buniello","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2021042700245761200_DMM044081C4","doi-asserted-by":"publisher","first-page":"e1006961","DOI":"10.1371\/journal.pgen.1006961","article-title":"Positional cloning of quantitative trait nucleotides for blood pressure and cardiac QT-interval by targeted CRISPR\/Cas9 editing of a novel long non-coding RNA","volume":"13","author":"Cheng","year":"2017","journal-title":"PLoS Genet."},{"key":"2021042700245761200_DMM044081C5","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.jacc.2007.02.067","article-title":"Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank","volume":"50","author":"Felker","year":"2007","journal-title":"J. Am. Coll. Cardiol."},{"key":"2021042700245761200_DMM044081C6","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/j.ahj.2009.07.024","article-title":"Red cell distribution width in heart failure: prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state","volume":"158","author":"F\u00f6rh\u00e9cz","year":"2009","journal-title":"Am. Heart J."},{"key":"2021042700245761200_DMM044081C7","doi-asserted-by":"publisher","first-page":"e80240","DOI":"10.1371\/journal.pone.0080240","article-title":"Increased red blood cell distribution width associates with cancer stage and prognosis in patients with lung cancer","volume":"8","author":"Koma","year":"2013","journal-title":"PLoS ONE"},{"key":"2021042700245761200_DMM044081C8","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1080\/00365510802213550","article-title":"Relationship between red blood cell distribution width and kidney function tests in a large cohort of unselected outpatients","volume":"68","author":"Lippi","year":"2008","journal-title":"Scand. J. Clin. Lab. Invest."},{"key":"2021042700245761200_DMM044081C9","doi-asserted-by":"publisher","first-page":"6","DOI":"10.4330\/wjc.v10.i2.6","article-title":"Red blood cell distribution width in heart failure: a narrative review","volume":"10","author":"Lippi","year":"2018","journal-title":"World J. Cardiol."},{"key":"2021042700245761200_DMM044081C10","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1186\/s12882-017-0766-4","article-title":"Red cell distribution width associated with adverse cardiovascular outcomes in patients with chronic kidney disease","volume":"18","author":"Lu","year":"2017","journal-title":"BMC Nephrol."},{"key":"2021042700245761200_DMM044081C11","doi-asserted-by":"publisher","first-page":"7150","DOI":"10.1021\/ac502040v","article-title":"MultiNotch MS3 enables accurate, sensitive, and multiplexed detection of differential expression across cancer cell line proteomes","volume":"86","author":"McAlister","year":"2014","journal-title":"Anal. Chem."},{"key":"2021042700245761200_DMM044081C12","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1093\/cvr\/cvv137","article-title":"Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats","volume":"107","author":"McCarthy","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"2021042700245761200_DMM044081C13","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1038\/260617a0","article-title":"Mechanical properties of vascular smooth muscle cells in situ","volume":"260","author":"Mulvany","year":"1976","journal-title":"Nature"},{"key":"2021042700245761200_DMM044081C14","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1093\/eurjhf\/hfp109","article-title":"Red blood cell distribution width predicts long-term outcome regardless of anaemia status in acute heart failure patients","volume":"11","author":"Pascual-Figal","year":"2009","journal-title":"Eur. J. Heart Fail"},{"key":"2021042700245761200_DMM044081C15","doi-asserted-by":"publisher","first-page":"e0185083","DOI":"10.1371\/journal.pone.0185083","article-title":"Red blood cell distribution width: genetic evidence for aging pathways in 116,666 volunteers","volume":"12","author":"Pilling","year":"2017","journal-title":"PLoS ONE"},{"key":"2021042700245761200_DMM044081C16","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1172\/JCI2251","article-title":"Construction of a double congenic strain to prove an epistatic interaction on blood pressure between rat chromosomes 2 and 10","volume":"101","author":"Rapp","year":"1998","journal-title":"J. Clin. Invest."},{"key":"2021042700245761200_DMM044081C17","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1161\/HYPERTENSIONAHA.107.097105","article-title":"Congenic interval mapping of RNO10 reveals a complex cluster of closely-linked genetic determinants of blood pressure","volume":"50","author":"Saad","year":"2007","journal-title":"Hypertension"},{"key":"2021042700245761200_DMM044081C18","doi-asserted-by":"publisher","first-page":"e40","DOI":"10.2337\/dc09-1707","article-title":"Higher red blood cell distribution width is associated with the metabolic syndrome: results of the Ibermutuamur CArdiovascular RIsk assessment study","volume":"33","author":"Sanchez-Chaparro","year":"2010","journal-title":"Diabetes Care"},{"key":"2021042700245761200_DMM044081C19","doi-asserted-by":"publisher","first-page":"e22378","DOI":"10.1002\/jcla.22378","article-title":"Red blood cell distribution width as a predictor of atrial fibrillation","volume":"32","author":"Shao","year":"2018","journal-title":"J. Clin. Lab. Anal."},{"key":"2021042700245761200_DMM044081C20","doi-asserted-by":"publisher","first-page":"9658216","DOI":"10.1155\/2018\/9658216","article-title":"The association between red blood cell distribution width and mortality in critically ill patients with acute kidney injury","volume":"2018","author":"Wang","year":"2018","journal-title":"Biomed. Res. Int."},{"key":"2021042700245761200_DMM044081C21","doi-asserted-by":"publisher","first-page":"e0198825","DOI":"10.1371\/journal.pone.0198825","article-title":"Red cell distribution width and renal outcome in patients with non-dialysis-dependent chronic kidney disease","volume":"13","author":"Yonemoto","year":"2018","journal-title":"PLoS ONE"}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dmm.044081","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.044081\/1973393\/dmm044081.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.044081\/2065840\/dmm_044081v2.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.044081\/2065840\/dmm_044081v2.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T22:44:21Z","timestamp":1621377861000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/doi\/10.1242\/dmm.044081\/267170\/Genetic-predisposition-for-increased-red-blood"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,1]]},"references-count":21,"URL":"https:\/\/doi.org\/10.1242\/dmm.044081","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"value":"1754-8411","type":"electronic"},{"value":"1754-8403","type":"print"}],"subject":[],"published":{"date-parts":[[2020,1,1]]},"article-number":"dmm.044081"}}