Impact of Superoxide Dismutase Genetic Polymorphism (SOD2 Val16Ala) and Superoxide Dismutase Level on Disease Severity in a Cohort of Egyptian Sickle Cell Disease Patients.

Background: Oxidative stress plays a pivotal role in the pathophysiology of sickle cell disease (SCD) and its associated disease complications. Superoxide Dismutases (SODs) are protective enzymes against oxidative stress. SOD2 deficiency results in the accumulation of oxidized red cell proteins, increased rate of hemoglobin oxidation, decreased red cell membrane deformability, and subsequently decreased red cells survival. Objective: The current study was designed to determine the effect of SOD2 Val16Ala gene polymorphism (rs4880) on SOD2 level and their possible impact on SCD disease severity in a cohort of Egyptian SCD patients. Methods: Genotyping SOD2 Val16Ala polymorphism by TaqMan allelic discrimination assay for hundred SCD patients and a hundred age-sex matched healthy controls revealed the genotypic and allelic frequencies of the studied polymorphism in the SCD patients were close to that of the controls. Results: Serum SOD2 level was significantly lower in those having the polymorphic genotypes (p=0.005). SOD2 level inversely correlates with the annual rate of hospitalization (r=-0.023, p= 0.038). Conclusion: SOD2 Val16Ala polymorphism was associated with low serum SOD2 level that may predict disease severity.

Protein Z and Endothelin-1 genetic polymorphisms in pediatric Egyptian sickle cell disease patients.

BACKGROUND: Sickle cell disease (SCD) is a monogenic disease associated with multisystem morbidity. Vasculopathy caused by delicate imbalance between coagulation and endothelial systems plays a pivotal role in disease course. As Protein Z and Endothelin-1 genetic polymorphisms may increase the thrombotic risk, the aim of the current work was to verify the possible impact of Protein Z (PROZ G79A) and Endothelin-1 (EDN1 G5665T) polymorphisms on the clinic-laboratory features of the SCD in a cohort of Egyptian pediatric patients. METHODS: Genotyping of Protein Z G79A and Endothelin-1 G5665T was carried out by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) assay for 100 SCD patients and 100 controls. RESULTS: Protein -Z G79A polymorphism was not associated with vascular complications in the studied SCD patients. Endothelin-1 G5665T polymorphism was associated with pulmonary dysfunction (pulmonary artery hypertension and acute chest syndrome) and severe vaso-occlusive crises (VOC). CONCLUSION: Endothelin-1 G5665T polymorphism could be considered as a molecular predictor for pulmonary dysfunction and severe VOC in SCD. Further researches with larger cohorts are recommended to understand the pathophysiology of SCD and to explain the inter-patients' variability of disease severity.

Diagnostic values of CD64, C-reactive protein and procalcitonin in ventilator-associated pneumonia in adult trauma patients: a pilot study.

BACKGROUND: Ventilator-associated pneumonia (VAP) is one of the most common nosocomial infections; however, its diagnosis remains difficult to establish in the critical care setting. We investigated the potential role of neutrophil CD64 (nCD64) expression as an early marker for the diagnosis of VAP. METHODS: Forty-nine consecutive patients with clinically suspected VAP were prospectively included in a single-center study. The levels of nCD64, C-reactive protein (CRP), and serum procalcitonin (PCT) were analyzed for diagnostic evaluation at the time of intubation (baseline), at day 0 (time of diagnosis), and at day 3. The receiver operating characteristic curves were analyzed to identify the ideal cutoff values. RESULTS: VAP was confirmed in 36 of 49 cases. In patients with and without VAP, the median levels (interquartile range, IQR) of nCD64 did not differ either at baseline [2.4 (IQR, 1.8-3.1) and 2.6 (IQR, 2.3-3.2), respectively; p=0.3] or at day 0 [2 (IQR, 2.5-3.0) and 2.6 (IQR, 2.4-2.9), respectively; p=0.8]. CRP showed the largest area under the curve (AUC) at day 3. The optimum cutoff value for CRP according to the maximum Youden index was 133 mg/dL. This cutoff value had 69% sensitivity and 76% specificity for predicting VAP; the AUC was 0.73 (95% CI, 0.59-0.85). The nCD64 and PCT values could not discriminate between the VAP and non-VAP groups either at day 0 or day 3. CONCLUSIONS: The results of this pilot study suggest that neutrophil CD64 measurement has a poor role in facilitating the diagnosis of VAP and thus may not be practically recommended to guide the administration of antibiotics when VAP is suspected.

Inducible nitric oxide synthase promoter polymorphism: a molecular susceptibility marker for vitiligo in Egyptians.

BACKGROUND: Vitiligo is a depigmentary disease characterized by loss of melanocytes from the skin and mucous membranes. The pathomechanism of vitiligo is still obscure. Inducible nitric oxide synthase (iNOS) produces very large amounts of nitric oxide (NO). Promotor polymorphisms within iNOS gene have been reported to be associated with overproduction of NO, which may induce melanocyte destruction. AIM: The current study aimed at investigating the possible association between iNOS gene polymorphism (-954 G/C and Ex 16+14 C/T) and susceptibility to non-segmental vitiligo in a cohort of Egyptians. METHODS: The study was conducted on 200 participants: 100 patients with vitiligo and 100 aged matched healthy controls. Polymerase chain reaction using restriction fragment length polymorphism method (PCR-RFLP) was used to identify the genotypes. RESULTS: Our results showed that iNOS -954 G/C heteromutant genotype (GC) was associated with increased risk of vitiligo (OR = 3.35, 95% CI = 1.77-6.33), and the risk increased when confined to females (OR = 7.4, 95% CI = 2.80-19.40). iNOS Ex 16 + 14 C/T heteromutant genotype (CT) conferred two folds increased risk of vitiligo (OR = 2.47, 95% CI = 1.39-4.37). Furthermore, the risk of vitiligo increased when the heteromutant genotype of iNOS -954 G/C (GC) was co-inherited with the wild genotype of iNOS Ex16+14 C/T (CC) (OR = 23.2, 95% CI = 3.04-177.21). CONCLUSIONS: Inducible nitric oxide synthase -954 G/C and Ex 16+14 C/T might be considered as genetic susceptibility markers for non-segmental vitiligo among Egyptians.

The clinical relevance and prognostic significance of adenosine triphosphate ATP-binding cassette (ABCB5) and multidrug resistance (MDR1) genes expression in acute leukemia: an Egyptian study.

AIM: Multidrug resistance (MDR1) represents a major obstacle in the chemotherapeutic treatment of acute leukemia (AL). Adenosine triphosphate ATP-binding cassette (ABCB5) and MDR1 genes are integral membrane proteins belonging to ATP-binding cassette transporters superfamily. PURPOSE: The present work aimed to investigate the impact of ABCB5 and MDR1 genes expression on the response to chemotherapy in a cohort of Egyptian AL patients. The study included 90 patients: 53 AML cases and 37 ALL cases in addition to 20 healthy volunteers as controls. METHODS: Quantitative assessment of MDR1 and ABCB5 genes expression was performed by quantitative real-time polymerase chain reaction. Additional prognostic molecular markers were determined as internal tandem duplications of the FLT3 gene (FLT3-ITD) and nucleophosmin gene mutation (NPM1) for AML cases, and mbcr-abl fusion transcript for B-ALL cases. RESULTS: In AML patients, ABCB5 and MDR1 expression levels did not differ significantly between de novo and relapsed cases and did not correlate with the overall survival or disease-free survival. AML patients were stratified according to the studied genetic markers, and complete remission rate was found to be more prominent in patients having low expression of MDR1 and ABCB5 genes together with mutated NPM1 gene. In ALL patients, ABCB5 gene expression level was significantly higher in relapsed cases and MDR1 gene expression was significantly higher in patients with resistant disease. CONCLUSION: In conclusion, the results obtained by the current study provide additional evidence of the role played by these genes as predictive factors for resistance of leukemic cells to chemotherapy and hence treatment outcome.

The link between genetic polymorphism of glutathione-S-transferases, GSTM1, and GSTT1 and diffuse large B-cell lymphoma in Egypt.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. A number of studies have examined the role of genetic polymorphisms in the risk of DLBCL, and several variants have been identified as potential susceptibility genes, of those glutathione-S-transferases T1 and M1 (GSTT1 and GSTM1). AIM OF THE WORK: The aim of the current study was to investigate the influence of inherited genetic polymorphisms of GSTM1 and GSTT1 genes on the susceptibility to DLBCL in Egypt. METHODS: Genotyping of the candidate genes was performed for 71 Egyptian DLBCL patients and 100 age- and gender-matched healthy controls by multiplex polymerase chain reaction technique. RESULTS: The frequencies of GSTT1 null, GSTM1 null, and dual null genotypes among DLBCL patients were 47.9, 52.1, and 23.9 % respectively. CONCLUSION: GSTT1 null genotype conferred almost fourfold increased risk of DLBCL (OR = 3.9, 95 % CI = 1.97-7.75), and the risk increased when confined to male patients (OR = 4.4, 95 % CI = 1.57-12.63), while GSTM1 null genotype was not associated with DLBCL risk. Further studies on the functional consequences of GSTT1 and GSTM1 genetic polymorphisms would pave the way to declare their role in the pathogenesis of DLBCL or as possible predictors for response to therapy.

FcγRIIa and FcγRIIIa genetic polymorphisms in a group of pediatric immune thrombocytopenic purpura in Egypt.

Immune thrombocytopenic purpura (ITP) is an acquired autoimmune disorder caused by the production of antiplatelet antibodies. The current case-control study aimed at detecting the frequency of FcγRIIa-131H/R and FcγRIIIa-158F/V genes polymorphism in Egyptian children with ITP as genetic markers for ITP risk, and to clear out their possible role in choosing the treatment protocols of ITP. To achieve this aim, FcγRIIa genotyping was tested by PCR-restriction fragment length polymorphism (RFLP) technique, whereas FcγRIIIa genotyping was tested by nested PCR followed RFLP analysis. The current case-control study was conducted on 92 children with ITP; 12 acute and 80 chronic cases and 90 controls. The V allele and FcγRIIIa FV heterotype were significantly higher in ITP patients and conferred increased ITP risk [odds ratio (OR) = 1.96 and 2.55, respectively]. The frequency of FcγRIIa H allele was significantly higher among chronic ITP patients. In conclusion, FcγRIIIa gene polymorphism may contribute to susceptibility to ITP. Moreover, analysis of the FcγR polymorphisms in ITP patients could influence the effectiveness of medications and selection of the line of treatment.