Polymorphism analysis in peroxiredoxin genes of beta thalassemia and sickle cell Disease patients: searching for new biological markers

Abstract

Peroxiredoxins (PRDX), the most abundant proteins in erythrocytes, are a family of thiol-specific enzymes which is involved in cellular antioxidant activity, since it acts on reduction and consequent degradation of hydrogen peroxide, organic hydroperoxides and peroxynitrite. In mammals this family has 6 members and is divided into three classes, the typical 2-Cys (comprised of PRDX 1 to 4), 2-Cys atypical (PRDX 5) and 1-Cys (PRDX 6). The action of these enzymes is of great importance for reducing the levels of reactive oxygen species (ROS), toxic metabolites generated endogenously and exogenously that at low levels operate in cell signaling, but at high levels can generate cellular damage, by attack in membrane, proteins and DNA, causing oxidative stress in cells. In hemolytic anemias, such as sickle cell disease and beta thalassemia, ROS seems to play an important role in the development of the disease. Sickle cell disease is a sickness caused by the point mutation in the beta-globin gene that replaces adenine for thymine and therefore there is an exchange of glutamic acid for valine in position 6 of the beta chain, leading to hydrophobic interactions between hemoglobins S and sickling erythrocytes. Beta-thalassemia is a hemoglobinopathy that occurs due to various mutations that lead to a reduction or absence of ²-globin production - by affecting the ² chain mRNA transcription, processing, translation, or polyadenylation - and the consequent reduction in hemoglobin A and excess ±-globin chains, with polymerization of them. In both diseases there is an increase in the production of ROS, mainly due to the instability of hemoglobin and iron overload. Therefore, the fight against oxidative stress is even more important in people who have these hemoglobinopathies. In a previous study by our research group, expression variations of PRDXs 1, 2 and 6 were analyzed in beta thalassemia and sickle cell disease patients. The goal of the current study is the identification of polymorphisms in the promoters and coding sequences of peroxiredoxins 1, 2 and 6, and the relationship of polymorphisms found with the expression variations of these enzymes in individuals with these hemmoglobinopathies.