Alpha-1 Antitrypsin and SERPINA1 gene Mutation As New Biomarker in Sickle Cell Disease

Sickle cell disease (SCD) has heterogeneous clinical picture and there are several pathway involved in SCD pathogenesis, and chronic inflammation and hemolysis are important hallmarks of the disease. Based on such points, there is a search for prognostic markers to establish possible sub-genotypes of the disease. The present study investigated the alpha-1 antitrypsin (AAT) levels, a serum glycoprotein inhibitor of proteases responsible for trigger inflammatory reactions, describing its associations with SERPINA1 gene polymorphisms, hematological and chemistry biomarkers, and clinical history in a group of SCD children in steady-state. The study was approved at FIOCRUZ research board and followed the principle of Declaration of Helsinki. A total of 356 steady state unrelated SCD patients were included at the present study and a control group (CG) compound by 100 unrelated healthy individuals sex and age matched with the patients group, which were from the same geographical origin. Patients age ranging 13.96+9.91 years of age, the AAT levels higher than the 50^th percentile (158.0 mg/mL) had significantly lower red blood cells (RBC) count (p=0.003), hemoglobin (Hb) (p=0.0002) and hematocrit (Hct) (0.0002) concentration, and higher white blood cells (WBC) (p=0.004) and neutrophils (p=0.0001) counts, and higher C-reactive protein (CRP) levels (p<0.0001), and lower urea levels (p=0.0003). AAT had significant negative correlation with RBC (r=-0.205, p=0.0001), Hb (r=-0.203, p=0.0001), Hct (r=-0.256, p<0.0001), high density lipoprotein cholesterol (HDL-C) (r=-0.205, p=0.0001), urea (r=-0.184, p=0.0005), creatinine (r=-134, p=0.012), and albumin (r=-0.135, p=0.011), and significant positive correlation with WBC (r=0.18, 0.0007), neutrophils (r=0.2297, p<0.0001), HbS (r=0.2874), total bilirubin (r=0.137, p=0.01), direct bilirubin (r=0.136, p=0.001), indirect bilirubin (r=0.115, p=0.032), lactate dehydrogenase (r=0.159, p=0.003), ferritin (r=0.1353, 9=0.011), CRP (r=0.355, p<0.0001). Patients with higher levels of AAT had clinical history of more than three infection episodes (OR=1.71, CI:1.05-2.65, p=0.02), gallstones presence (OR=1.75, CI:1.03-2.97, p=0.02), and received more blood therapy (OR=2.35, CI:1.51-3.65, p=0.0001).The SERPINA1 gene polymorphisms were analyzed in 126 SCD patients and 100 CG individuals, the protease inhibitor (Pi)*MM or wide type genotype was find in 115 (91.3%) of SCD patients and 92 (92%) of CG; the PI*SS genotype was find in 2 (1.6%) SCD patients and in none individual of the CG; the PI*MS genotype was find in 9 (7.1%) SCD patients and in 6 (6%) CG individuals; and the PI*MZ genotype was find in 2 (2%) CG individuals. Ours results suggest that the AAT may be considerer as a marker of SCD patients’ outcome, once increased levels is related to stress situation, anti-inflammatory and inhibitory proteases properties and may act as a physiological and cytoprotective regulator influencing the severity of SCD. Our results related to SERPINA1 genotypes emphasize the role of the mutant allele in decrease the AAT production what may represent a risk factor. Additional studies should be carried out in order to investigate mechanisms throughout the AAT can induce several important events in the SCD pathogenesis.