Associação entre as variantes dos genes de receptores ativados por proliferação de peroxissomos (PPAR) e a variante regulatória dos genes da alfa-globina (HBA) com aspectos laboratoriais e clínicos em indivíduos com anemia falciforme

Abstract

Sickle cell anemia (SCA) is a widely distributed hereditary hemoglobinopathy resulting from the c.20A>T mutation in the HBB gene, which leads to a structural alteration in betaglobin, p.Glu7Val, forming hemoglobin S (HbS). The polymerization of HbS in SCA causes intravascular hemolysis, oxidative stress and inflammatory responses, culminating in microvascular vaso-occlusion. There are reports in the literature that polymorphisms in the regulatory region of the alpha-globin genes, such as rs11865131 within the NPRL3 gene, modulate the expression of the HBA1/2 genes and abrogate the effect of co-inheritance of alphathalassemia (alpha-thal) on hematological parameters of SCA. Peroxisome proliferatoractivated receptors (PPARs) are transcription factors that regulate a series of genes associated with inflammation, oxidative stress, hepatic metabolism and fatty acids and lipoproteins, among other functions. This study investigated the association of polymorphisms in the PPAR genes and the regulatory variant rs11865131 of the HBA1/2 genes with laboratory and clinical variables in individuals with SCA, controlling for the effects of hydroxyurea (HU) therapy and the presence of alpha-thal. Genotyping was performed by qPCR with TaqMan® probes for polymorphisms in PPAR genes and rs11865131 and gapPCR for deletional alpha-thal. Laboratory and clinical data were collected from medical records and analyzed by appropriate statistical tests considering a significance level of 0.05. The study involved 110 individuals with SCA born between 01/01/1998 and 12/31/2014 and followed at the Regional Blood Center of Governador Valadares, Minas Gerais, Brazil. Of the participants, 53.6% were male and 54.55% were on HU therapy. Clinical events in the previous year included painful crises in 48.1%, hospitalizations in 24.32% and blood transfusions in 31.65%. In the analysis of PPAR polymorphisms, the A-rs4253747 variant of PPARA was associated with increased total bilirubin, and the G-rs709158 variant of PPARG with increased lactate dehydrogenase, suggesting that these variants may influence the severity of AF since they are associated with hemolytic markers. HU therapy improved red blood cell markers and lipid parameters, reducing hemolysis and inflammation. The impact of HU therapy was more significant for the change in lipid parameters when individuals with AF carried specific alleles of the PPAR variants. Alphathal co-inheritance was associated with reduced mean corpuscular hemoglobin (MCH), but without significant impact on clinical parameters. The A-rs11865131 variant, which regulates HBA1/2 genes, increased hemoglobin only in the group with alpha-thal co-inheritance without affecting mean corpuscular volume and MCH, and is a risk factor for hemolysis markers (total and indirect bilirubin). This study highlights that variants in the PPAR genes and the rs11865131 SNP, which regulates HBA1/2 genes, affect laboratory markers of severity in SCA. Validation in larger populations is essential to confirm these findings and their reproducibility and association with clinical outcomes.