Evaluation of Alpha-1 Antitrypsin Levels and SERPINA1 Gene Polymorphisms in Sickle Cell Disease

Abstract

Alpha-1 antitrypsin (AAT) is an inhibitor of neutrophil elastase and a member of the serine proteinase inhibitor (serpin) superfamily, and little is known about its activity in sickle cell disease (SCD). We hypothesize that AAT may undergo changes in SCD because of the high oxidative stress and inflammation associated with the disease. We have found high AAT levels in SCD patients compared to controls, while mutant genotypes of SERPINA1 gene had decreased AAT levels, in both groups. AAT showed negative correlation with red blood cells, hemoglobin (Hb), hematocrit, high-density lipoprotein cholesterol, urea, creatinine, and albumin and was positively correlated with mean corpuscular Hb concentration, white blood cells, neutrophils, Hb S, bilirubin, lactate dehydrogenase, ferritin, and C-reactive protein. Patients with higher levels of AAT had more infection episodes (OR = 1.71, CI: 1.05–2.65, p = 0.02), gallstones (OR = 1.75, CI: 1.03–2.97, p = 0.02), and had more blood transfusions (OR = 2.35, CI: 1.51–3.65, p = 0.0001). Our data on AAT association with laboratory indices of hemolysis and inflammation suggest that it may be positively associated with SCD severity; the negative correlations with renal parameters suggest a cytoprotective mechanism in SCD patients. In summary, AAT may need to be included in studies related to SCD and in the discussion of further therapeutic strategies.

Sickle Cell Anemia: Variants in the CYP2D6, CAT, and SLC14A1 Genes Are Associated With Improved Hydroxyurea Response

“…In the present study, we found an association between the variant A allele of the polymorphism rs2298720 and elevated creatinine and reduced AAT concentrations in patients undergoing HU treatment. This results corroborate our previous findings, which observed a negative correlation between AAT and creatinine in patients with sickle cell disease, i.e., with HbSS, HbSC, or HbSβ + ( Carvalho et al, 2017 ). Moreover, it was reported that the accumulation of urea, an HU analog, might occur in human urothelial cells due to low SLC14A1 expression ( Hou et al, 2017 ).…”

Sickle cell disease: A distinction of two most frequent genotypes (HbSS and HbSC)

“…Our cohort of patients with previous history of VO exhibited laboratory parameters associated to anemia and systemic inflammation. Increased AAT levels were found to be associated to infections, gallstones and blood therapy in SCD [40]; moreover, C-RP levels were progressively increasing as SCA severity score was higher [41]. Our findings are in agreement with the pathophysiological mechanism of VO due to i) heightened ability of sickle RBC to adhere to the vascular endothelium and promote activation of endothelial cells and leukocytes and ii) sickle RBC have the lifespan shortened which also contributes to anemia [42].…”

“…These markers are suggestive of the main underlying pathophysiological mechanisms of the disease, which often overlap [1]. In the first cluster the association of NOm and hemolytic markers reinforces the role of endothelial dysfunction [13,44], while in the second the association of leukocytes counts and CRP and AAT highlights the role of inflammation [40,41] and in the last cluster, grouping of RBC counts along with Hb, Ht and iron levels suggest the importance of anemia [21,22]. Curiously HbF was differentially clustered in each genotype.…”

Proteomic analysis of seminal plasma from bilateral varicocele patients indicates an oxidative state and increased inflammatory response

“…Among the inflammatory proteins, SERPINA1 is an acute-phase protein and responsible for the inhibition of proteases involved in stimulating the inflammatory response. During inflammation, their expression levels are high in plasma 44. Zylbersztejn et al 16.…”