Genetic predisposition for increased red blood cell distribution width is an early risk factor for cardiovascular and renal comorbidities.

Xi Cheng,Cameron G Mccarthy,Sarah Galla,Ahmad Alimadadi,Bina Joe,Blair Mell,Saroj Chakraborty,Venkatesha Basrur

doi:10.1242/dmm.044081

Abstract

ABSTRACTRed 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) that 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, which 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 50 bp deletion in a non-coding region, and 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 outcome.

Highlights

Red blood cell distribution width (RDW) is a measure of the range of variation in size and volume of red blood cells (RBCs)
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
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

Summary

Introduction

Red blood cell distribution width (RDW) is a measure of the range of variation in size and volume of red blood cells (RBCs). Increased RDW, as reported by the standard complete blood count, represents an increased heterogeneity of RBCs and it is known as anisocytosis, referring to a patient’s red blood cells of unequal size. Increased RDW is noted as a feature associated with a variety of diseases including cancer (Koma et al 2013) and metabolic syndrome (Sanchez-Chaparro et al 2010). Increased RDW has been observed to co-exist with multiple cardiovascular disorders, such as hypertension (Bilal et al 2016), atrial fibrillation (Shao et al 2018) and heart failure (Lippi et al 2018). Little is known regarding the significance of this association. Lack of animal models with a prominent RDW phenotype precludes studies from examining the relationship between RDW and the co-morbid cardiovascular conditions

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Conclusion