Computational Analysis of Deleterious nsSNPs in INS Gene Associated with Permanent Neonatal Diabetes Mellitus.

Insulin gene mutations affect the structure of insulin and are considered a leading cause of neonatal diabetes and permanent neonatal diabetes mellitus PNDM. These mutations can affect the production and secretion of insulin, resulting in inadequate insulin levels and subsequent hyperglycemia. Early discovery or prediction of PNDM can aid in better management and treatment. The current study identified potential deleterious non-synonymous single nucleotide polymorphisms nsSNPs in the INS gene. The analysis of the nsSNPs in the INS gene was conducted using bioinformatics tools by implementing computational algorithms including SIFT, PolyPhen2, SNAP2, SNPs & GO, PhD-SNP, MutPred2, I-Mutant, MuPro, and HOPE tools to investigate the prediction of the potential association between nsSNPs in the INS gene and PNDM. Three mutations, C96Y, P52R, and C96R, were shown to potentially reduce the stability and function of the INS protein. These mutants were subjected to MDSs for structural analysis. Results suggested that these three potential pathogenic mutations may affect the stability and functionality of the insulin protein encoded by the INS gene. Therefore, these changes may influence the development of PNDM. Further researches are required to fully understand the various effects of mutations in the INS gene on insulin synthesis and function. These data can aid in genetic testing for PNDM to evaluate its risk and create treatment and prevention strategies in personalized medicine.

Platelet Glycoprotein IIIa PlA1/PlA2 Polymorphism Modulates the Risk of Myocardial Infarction in Non-Diabetics.

Background: Genetic polymorphisms of platelet glycoprotein IIIa (GPIIIa gene) have been investigated intensively in several thrombotic diseases, but their role in cardiovascular diseases remains controversial. This study aimed to investigate the association between platelet glycoprotein IIIa PlA1/PlA2 polymorphism and susceptibility to myocardial infarction in non-diabetics. Methods: A total of 200 participants were recruited for the study, 100 non-diabetic patients with myocardial infarction and 100 apparently healthy volunteers as a control group. GPIIIa PlA1/PlA2 polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism. Results: The distribution of GPIIIa PlA1/PlA2 polymorphic genotypes among the study groups was significantly different (P value = 0.00). The PlA1/PlA2 and PlA2/PlA2 genotypes were more frequent in the patients with myocardial infarction while the genotype PlA1/PlA1 was more prevalent in the control group. There was a statistically significant association between the PlA1/PlA1 genotype and reduced risk of both ST-segment elevation myocardial infarction (odds ratio (OR) = 0.19; 95% confidence interval (CI): 0.09 - 0.34, P value = 0.00) and non-ST-segment elevation myocardial infarction (OR = 0.21; 95% CI: 0.09 - 0.45, P value = 0.00). The genotype PlA1/PlA2 was found to be associated with an increased risk of both types of myocardial infarction (OR = 6.0; 95% CI: 2.61 - 13.8, P value = 0.00 for ST-segment elevation myocardial infarction and OR = 6.65; 95% CI: 2.69 - 16.45, P value = 0.00 for non- ST-segment elevation myocardial infarction. In the patients carrying the PlA1/PlA2 genotype, the risk of ST-segment elevation myocardial infarction was increased to about 14 folds in the presence of family history (OR: 13.57, 95% CI: 1.42 - 130.03, P value = 0.02), and the risk of non-ST-segment elevation myocardial infarction increased to about 18 folds in the smokers carrying the genotype PlA2/PlA2 (OR: 17.63, 95% CI: 0.96 - 324.70, P value = 0.05). Conclusions: The GPIII PlA1/PlA1 genotype is associated with a reduced risk of ST-segment elevation and non-ST-segment elevation myocardial infarction, while PlA1/PlA2 is associated with an increased risk of both types of myocardial infarction.

In Silico Evaluation of the Potential Association of the Pathogenic Mutations of Alpha Synuclein Protein with Induction of Synucleinopathies.

Alpha synuclein (α-Syn) is a neuronal protein encoded by the SNCA gene and is involved in the development of Parkinson's disease (PD). The objective of this study was to examine in silico the functional implications of non-synonymous single nucleotide polymorphisms (nsSNPs) in the SNCA gene. We used a range of computational algorithms such as sequence conservation, structural analysis, physicochemical properties, and machine learning. The sequence of the SNCA gene was analyzed, resulting in the mapping of 42,272 SNPs that are classified into different functional categories. A total of 177 nsSNPs were identified within the coding region; there were 20 variants that may influence the α-Syn protein structure and function. This identification was made by employing different analytical tools including SIFT, PolyPhen2, Mut-pred, SNAP2, PANTHER, PhD-SNP, SNP&Go, MUpro, Cosurf, I-Mut, and HOPE. Three mutations, V82A, K80E, and E46K, were selected for further examinations due to their spatial positioning within the α-Syn as determined by PyMol. Results indicated that these mutations may affect the stability and function of α-Syn. Then, a molecular dynamics simulation was conducted for the SNCA wildtype and the four mutant variants (p.A18G, p.V82A, p.K80E, and p.E46K). The simulation examined temperature, pressure, density, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), and radius of gyration (Rg). The data indicate that the mutations p.V82A, p.K80E, and p.E46K reduce the stability and functionality of α-Syn. These findings highlight the importance of understanding the impact of nsSNPs on α-syn structure and function. Our results required verifications in further protein functional and case-control studies. After being verified these findings can be used in genetic testing for the early diagnosis of PD, the evaluation of the risk factors, and therapeutic approaches.

Multi-factorial Mechanism Behind COVID-19 Related Thrombosis.

Background: Thrombosis plays a crucial role in the morbidity and mortality of coronavirus disease-19 (COVID-19). About one-third of COVID-19 patients experience a thrombotic event, most commonly pulmonary embolism. Based on published data, the mechanism of thrombosis in COVID-19 patients seems to be multi-factorial. Methods: In this article, we reviewed the publsihed data concerning with thrombosis in COVID-19 and summarized the predisposing factors and the mechanisms behind COVID-19 related thrombosis. Results: Inflammatory response to SARS-CoV-2 and the consequent hyperviscosity thought to cause endothelial damage and initiate coagulation. Furthermore, inflammation promotes platelet activation and exerts a pathogenic effect on endothelial cells. The presence of anticardiolipin and anti-ß2-glycoprotein antibodies in some patients with COVID-19 suggests that SARS-CoV-2, like many other viral infections, induces the formation of antiphospholipid antibodies, which provoke hypercoagulability. Thrombophilic mutations, mainly factor V Leiden and prothrombin G20201A mutations, can be a contributing factor in the development of thrombosis in COVID-19 patients, and they are associated with increased disease severity and pulmonary embolism. However, the research concerning with the association of thrombophilic mutations with COVID-19 related thrombosis showed conflict results. Conclusion: The mechanism of thrombosis in COVID-19 patients seems to be multifactorial. Endothelial damage, antiphospholipid antibodies, inflammation, hyperviscosity, and thrombophilic mutations are the main factors that predispose COVID-19 patients to. thrombosis.

Angiotensin-converting enzyme insertion/deletion polymorphism is not associated with vasoocclusive complications of sickle cell anemia.

CONTEXT: Sickle cell anemia (SCA) is a group of hemoglobin disorders in which the sickle ß-globin gene is inherited. It is associated with many complications; most of them are related to thrombotic events. AIM: This study aimed to investigate the association between angiotensin converting enzyme (ACE) insertion/deletion polymorphism and complications of SCA. SETTINGS AND DESIGN: A case-control study was conducted in Khartoum state. SUBJECTS AND METHODS: A total of 50 patients with SCA and 40 healthy volunteers as a control group were enrolled in this study. Three milliliters of ethylenediamine tetraacetic acid anticoagulated blood were collected from each subject, DNA was extracted by salting-out method, and target DNA regions of the ACE gene were amplified using allele-specific polymerase chain reaction. STATISTICAL ANALYSIS USED: Data of this study was analyzed by Statistical Package for Social Sciences. Frequency of qualitative variables was calculated, and correlation was tested by Chi-square test. Regression was used to investigate the association between the polymorphism and complications of SCA. RESULTS: The frequencies of the DD, ID, and II genotypes were 42%, 50%, and 8%, respectively, for patients, whereas in the control group, it was 80% for DD genotype and 20% for ID, while II genotype was totally absent. The regression analysis showed no statistically significant association between the disease complications and each of the ACE polymorphic genotypes. CONCLUSION: No statistically significant association was found between ACE polymorphism and complications of SCA.

The role of erythrocyte enzyme glucose-6-phosphate dehydrogenase (G6PD) deficiency in the pathogenesis of anemia in patients on hemodialysis.

Anemia is a common feature among patients with chronic renal failure (CRF). Low activity of the erythrocyte enzyme glucose-6-phosphate dehydrogenase (G6PD), which plays a major role in protecting red blood cells against oxidative agents, has been described as one of the contributing factors to anemia in patients with CRF treated with hemodialysis (HD). In this study, blood samples were randomly collected from 65 patients on HD and investigated for G6PD deficiency using the methemoglobin reduction test. The hemoglobin (Hb) concentration, packed cell volume (PCV), red blood cells (RBCs) count and reticulocyte count were determined in all the samples. Our results showed that 39 of 65 patients (60%) on HD had low G6PD activity and 26 (40%) patients had normal activity; 59% of the patients with low G6PD activity were males. The mean Hb, PCV and RBCs counts were lower in patients with low G6PD activity than in those with normal G6PD activity, but the difference was not statistically significant. Likewise, no statistically significant difference was found in the reticulocyte count in patients with low G6PD activity and in those with normal G6PD activity. The low G6PD activity that was found in a large proportion of patients on HD seems to be the result of enzyme inhibition rather than deficiency. No statistically significant difference was found in anemia parameters between patients with and without G6PD deficiency.