  Citation: Edwards, O.; Burris, A.; Lua, J.; Wilkie, D.J.; Ezenwa, M.O.; Doré, S. Influence of Haptoglobin Polymorphism on Stroke in Sickle Cell Disease Patients. Genes 2022, 13, 144. https://doi.org/10.3390/ genes13010144 Academic Editors: Svetlana A. Limborska and Ivan B. Filippenkov Received: 1 December 2021 Accepted: 7 January 2022 Published: 14 January 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). genes G C A T T A C G G C A T Review Influence of Haptoglobin Polymorphism on Stroke in Sickle Cell Disease Patients Olivia Edwards 1 , Alicia Burris 1 , Josh Lua 1 , Diana J. Wilkie 2 , Miriam O. Ezenwa 2 and Sylvain Doré 1,3, * 1 Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL 32610, USA; oliviaedwards@ufl.edu (O.E.); aliciaburris@ufl.edu (A.B.); joshlua@ufl.edu (J.L.) 2 Department of Biobehavioral Nursing Science, University of Florida College of Nursing, Gainesville, FL 32610, USA; diwilkie@ufl.edu (D.J.W.); moezenwa@ufl.edu (M.O.E.) 3 Departments of Neurology, Psychiatry, Pharmaceutics, and Neuroscience, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA * Correspondence: sdore@ufl.edu Abstract: This review outlines the current clinical research investigating how the haptoglobin (Hp) genetic polymorphism and stroke occurrence are implicated in sickle cell disease (SCD) pathophysi- ology. Hp is a blood serum glycoprotein responsible for binding and removing toxic free hemoglobin from the vasculature. The role of Hp in patients with SCD is critical in combating blood toxicity, inflammation, oxidative stress, and even stroke. Ischemic stroke occurs when a blocked vessel decreases oxygen delivery in the blood to cerebral tissue and is commonly associated with SCD. Due to the malformed red blood cells of sickle hemoglobin S, blockage of blood flow is much more prevalent in patients with SCD. This review is the first to evaluate the role of the Hp polymorphism in the incidence of stroke in patients with SCD. Overall, the data compiled in this review suggest that further studies should be conducted to reveal and evaluate potential clinical advancements for gene therapy and Hp infusions. Keywords: brain ischemia; genotype; hemolytic anemia; hospitalization; inflammation; mini-stroke; oxidative stress; pain crisis; silent cerebral infarction; therapy; vaso-occlusion 1. Introduction 1.1. Sickle Cell Disease Sickle cell disease (SCD) is a group of autosomal recessive disorders that affect an estimated 20 to 25 million people worldwide [1], making it the most prevalent monogenic disorder and a serious public health concern. Inheritance of this disorder is concentrated in sub-Saharan African, South Asian, Middle Eastern, and Mediterranean regions [2,3]. Due to the recessive-trait nature of SCD, even larger populations carry sickle cell trait, maintaining the chances that SCD will be passed on through generations. Every year, an estimated 300,000 infants are born with SCD worldwide, adding to the existing millions of patients seeking treatment [2]. SCD is a hemolytic disorder caused by a range of mutations in the gene responsible for coding the β-globin (HBB) subunits of hemoglobin (Hb). These mutations usually result in abnormal versions of Hb, which are capable of polymerizing, leading to malformed, sickle-shaped red blood cells (RBCs). SCD is a form of hemolytic anemia, a class of disorders characterized by high rates of hemolysis. As these deformed and rigid RBCs travel through the vasculature and supply major organs, high levels of hemolysis occur, triggering signaling pathways that can lead to oxidative stress, free radical formation, chronic pain crises, and other detrimental symptoms that are characteristic of SCD. The resulting byproducts of hemolysis are of particular concern due to their high natural toxicity to the body’s life-sustaining organs. Free heme, a direct product of Hb destruction, is the main culprit of many symptoms associated with SCD. Genes 2022, 13, 144. https://doi.org/10.3390/genes13010144 https://www.mdpi.com/journal/genes