Abstract
β-Thalassemia is one of the most prevalent forms of congenital blood disorders characterized by reduced hemoglobin levels with severe complications, affecting all dimensions of life. The mechanisms underlying the phenotypic heterogeneity of β-thalassemia are still poorly understood. We aimed to work over metabolite biomarkers to improve mechanistic understanding of phenotypic heterogeneity and hence better management of disorder at different levels. Untargeted serum metabolites were analyzed after protein precipitation and SPE (solid phase extraction) from 100 β-thalassemia patients and 61 healthy controls using GC-MS. 40 metabolites were identified having a significance difference between these two groups at probability of 0.05 and fold change >1.5. Out of these 40 metabolites, 17 were up-regulated while 23 were down-regulated. PCA and PLS-DA model was also created that revealed a fine separation with a sensitivity of 70% and specificity of 100% on external validation of samples. Metabolic pathway analysis revealed alteration in multiple pathways including glycolysis, pyruvate, propanoate, glycerophospholipid, galactose, fatty acid, starch and sucrose metabolism along with fatty acid elongation in mitochondria, glycerolipid, glyoxylate and dicarboxylate metabolism pointing towards the shift of metabolism in β-thalassemia patients in comparison to healthy individuals.
Highlights
Syed Ghulam Musharraf[1,2], Ayesha Iqbal[2], Saqib Hussain Ansari[3], Sadia Parveen[3], Ishtiaq Ahmad Khan2 & Amna Jabbar Siddiqui[1] β-Thalassemia is one of the most prevalent forms of congenital blood disorders characterized by reduced hemoglobin levels with severe complications, affecting all dimensions of life
Statistical and multivariate data investigation i.e. Heatmap, Principal component analysis (PCA) plot and Partial Least Square Discriminant Analysis (PLSDA) plot was carried out using Mass Profiler Professional (MPP) software in order to identify comparative and statistically significant metabolites between healthy and β-thalassemia samples
We identified several pathways some were generated from list of metabolites that were up-regulated in β-thalassemia, including fatty acid elongation in mitochondria, glycolysis or gluconeogenesis, pyruvate, propanoate, glycerophospholipid, galactose, fatty acid biosynthesis and metabolism, starch and sucrose metabolism that may be amplified in these patients
Summary
Syed Ghulam Musharraf[1,2], Ayesha Iqbal[2], Saqib Hussain Ansari[3], Sadia Parveen[3], Ishtiaq Ahmad Khan2 & Amna Jabbar Siddiqui[1] β-Thalassemia is one of the most prevalent forms of congenital blood disorders characterized by reduced hemoglobin levels with severe complications, affecting all dimensions of life. We aimed to work over metabolite biomarkers to improve mechanistic understanding of phenotypic heterogeneity and better management of disorder at different levels. 40 metabolites were identified having a significance difference between these two groups at probability of 0.05 and fold change >1.5. Out of these 40 metabolites, 17 were up-regulated while 23 were down-regulated. While in Pakistan, the most common mutation responsible for causing this blood disease is IVS1-55. In β-thalassemia, there is an imbalance in α/β-globin ratio and excessive α-globins possibly causes oxidative damage to membrane lipids and proteins of red cell in the form of irreversible hemichromes and increases intracellular calcium, causing the significant increase in destruction of RBCs and anaemia[6]. Metabolomics has been used as potential biomarkers in organ transplantation and immunosuppressant toxicity[9], assessing pathogenesis of lung diseases[10,11], toxicology[12], drug discovery and precision medicine[13] and cancer biology[14,15,16]
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