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Thiopurine Methyltransferase Genotyping in Childhood Acute Lymphoblastic Leukemia Patients in Gaza Strip
Get PDFBackground: The genetic polymorphism of thiopurine methyltransferase (TPMT) is well characterized in most populations. Three common polymorphic alleles are associated with impaired activity of the enzyme. These are TPMT*2 (238G>C), TPMT*3A (460G>A, 719A>G) and TPMT*3C (719A>G). Objective: The aim of the present study was to determine the frequency of the functional TPMT polymorphisms and their association with the occurrence of adverse events, during 6-mercaptopurine therapy in pediatric acute lymphoblastic leukemic (ALL) patients in Gaza Strip. Methods:A total of 56 DNA samples from all pediatric ALL patients admitted to the pediatric hematology departments of Gazastrip hospitals were analyzed. Genomic DNA from peripheral blood leukocytes was isolated and the TPMT*2, TPMT*3A and TPMT*3C allelic polymorphism was determined by PCR- RFLP and allele specific PCR technique. Results: No TPMT*2, *3C mutant alleles were detected. Only the TPMT*3A allele was detected in one patient out of 56 DNA samples of pediatric ALL patients inGazastrip. Thus, frequency of TPMT*3A allele was 0.89%. Fourteen patients of ALL were suffering from mylotoxicity during 6MP therapy. From our results, no significant association could be established between clinical and laboratory data and/or the presence of the mutation in TPMT gene. The calculated incidence of ALL in children in Gaza Strip is 2 cases per 100000 children. The incidence of ALL is higher in males than in females. The mean age of ALL incidences in Gaza Strip is 4.4 ± 2.6 years. Conclusion: This is the first analysis of the polymorphisms of the TPMT gene in childhood ALL patients in Gaza Strip. Other types of mutation in TPMT gene may be responsible for the observed mylotoxicity among the investigated patients. Factors other than TPMT polymorphisms may also be responsible for the development of toxicity. Therefore, more studies are recommended to be performed in order to investigate such factors
الطفرة احادية النيكلوتيدة (e23k) للجين kcnj11 وعوامل خطر اخرى مرتبطة بمرضى السكري من النوع الثاني بمدينة غزة-فلسطين
No full textType 2 diabetes mellitus (T2DM) is a multifactorial disease in which environmental triggers interact with genetic variants in the predisposition to the disease. KATP channels regulate insulin secretion by coupling the metabolic state of the cell to membrane potential. (KATP) channels in pancreatic β-cells comprise a pore-forming, K+ inward rectifier (Kir6.2) encoded by the KCNJ11 gene. A common single nucleotide polymorphism E23K of the KCNJ11 gene has been associated with T2DM in different population. The role of this polymorphism was not previously tackled in Palestine. Therefore, the aim of this study is to assess the (E23K) SNP in KCNJ11 gene as a possible contributor to T2DM among Gaza City (GC) patients. Also to consider relation between E23K SNP and other environmental/physical risk factors for T2DM. In order to achieve this goal, two hundred male and female individuals were examined: 100 T2DM patients and 100 control individuals. The glucose level was determined, and DNA was extracted from whole blood samples for all subjects. The groups were genotyped of SNP (E23K) by PCR/RFLP technique using the BanII restriction enzyme. A questionnaire was completed to evaluate the role of physical and environmental risk factors for T2DM. The results of the study showed that there was a strong statistically significant relation between the distribution of the E23K polymorphism and T2DM (P=0.000). Fourty-three percent of cases were E/K compared to 29% of controls; and 15% of cases were K/K compared to 3% of controls. Obesity, persistent stress, absence of physical activity and low level of education are also statically significant related to T2DM in the GC (P=0.000). Moreover, the mean fasting blood sugar level was statistically higher among the cases than the control, and particularly among the cases having any of the upper mentioned genetic and\or environmental risks factors (P= 0.000). The highest percentage of cases with family history of T2DM was among those of E/K (88.4%) compared to (73.3%) of K/K, and (37.8%) in E/E. This distribution was not statistically significant (P=0.191). In a conclusion risk factors that are significantly implicated with T2DM in diabetic patients in the GC include the E23K polymorphism, obesity, stress, absence of physical activity, and low level of education. The inheritance of the K allele predisposes for T2DM , provided that other genetic or/and physical and environmental risk factors to be present
تحديد الطرز الجينية للبكتريا الملوية البوابية وتحديد مدى مقاومتها للكلاريثرومايسين للمرضى المصابين في قطاع غزة - فلسطين
No full textHelicobacter pylori is the most widely spread bacteria world wide, it infects more than half of the world population. It is associated with many different gastric and extra-gastric diseases. The bacterium was classified by the international agency for cancer research and the WHO as a definite class I carcinogen in 1994. The wide range of its pathogenicity may be due to host, environmental, and bacterial virulence factors. Some genes like the cagA and vacA are responsible for the pathogenicity of the organism. The vacA gene exhibits a highly mosaic and recombination between two different regions, the signal and the mid region which may be associated with the highly difference in associated disease in association with the host and environmental factors. Clarithromycin is the key component of treatment where the resistance to this antibiotic results in treatment failure. Therefore, the aim of this study was to determine the genotypes of vacA and cagA, and to evaluate clarithromycin resistance in H. pylori infected patients in Gaza strip. In order to achieve this goal, two different biopsy samples from different sites of the antrum were collected from 94 patients where just one biopsy sample was collected from seven patients. The first biopsy sample was extracted for PCR to determine the vacA and cagA genotypes. (The second biopsy was formalin-fixed and paraffin-embedded, five - 4 µ thick slides were used for FISH for clarithromycin resistance evaluation, the other two slides were used for Giemsa stain and Haematoxyline & Eosin stain for identification of H. pylori and histopathological assessment). Clinical diagnosis and clinical information were recorded from the index for every patient. The results of the study showed that the most predominant vacA was s2m2 (43.2%), and the gene cagA was present in 30.8% of infected cases. The frequency of mutations were found (3.9%: A2143G), (3.9%: A2144G), (0.0%: A2143C) and 19.6% were not typed by the most common three mutations (A2143G, A2144G and A2143C ) or the wild type. There is no statistically significant relationship between the H. pylori infection or genotypes of H. pylori and the clinical diagnosis of gastroscope. The results revealed that there was statistically significant correlation between H. pylori infection, and the degree of mucosal inflammation (P = 0.004). There is also statistically significant correlation between H. pylori infected patients and Whitehead degree of gastritis index (P = 0.032). Moreover there is statistically significant correlation between the genotype s1m1 and atrophy (P = 0.006), and almost close to Intestinal metaplasia (P = 0.052). In conclusion the genotypes of H. pylori cagA and vacA in Gaza strip are similar to that in our region (Egypt, Jordan, "Israel"). There was no statistically significant relationship between the genotypes of H. pylori and the clinical diagnosis of gastroscope and this may be due to other environmental or dietary factors
Allelic Variants of CYP2C9 and VKORC1 Genes and their Relation to Warfarin Metabolism in Patients Under Warfarin Therapy in Gaza Strip
No full textBackground: Warfarin is the most widely prescribed oral anticoagulant for thromboembolic therapy, patient management is difficult because of significant differences in metabolic rates as a result of allelic variation in its metabolizing enzyme. CYP2C9 gene encoding the enzyme that catalyzes the conversion of Warfarin to inactive metabolites, and the VKORC1 gene encoding the enzyme responsible for reducing vitamin K 2,3-epoxide to the enzymatically activated form. Three single nucleotide polymorphisms (SNPs), two in the CYP2C9 gene and one in the VKORC1 gene, have been found to play key roles in determining the effect of Warfarin therapy on coagulation. The presence of CYP2C9*2 and CYP2C9*3 variant alleles decrease the enzymatic activity which cause the elongation of half-life and reduced rate of clearance of Warfarin. Objectives: The aim of this study was to determine the allelic varints of CYP2C9 gene (alleles *1, *2 and *3) and VKORC1 (alleles 1639-G and 1639-A) in Gaza strip, and to determine the relation between the Warfarin anticoagulation and the genotype of the two genes CYP2C9 and VKORC1. Methods: Whole blood samples were collected from 101 patients under Warfarin therapy who visited anti-coagulation clinics of Alshifa and Gaza European hospitals then subjected to DNA extraction. Allelic variants of CYP2C9 and VKORC1 genes were determined by PCR-RFLP technique. Also sodium citrated whole blood samples were collected and plasma were separated for the determination of their Prothrombin time/international normalized ratio (PT/INR) level in order to establish a relationship between the CYP2C9 and VKORC1 allelic variants and the Warfarin anticoagulation. Results: It was found that none of the patients who are receiving the Warfarin has achieved the therapeutic range during the first month of Warfarin medication. There is a statistically significant difference in average INR between patients who have homozygote or heterozygote CYP2C9*2 and that who have the wild type CYP2C9*1/*1 and VKORC1(G/G) genotypes (3.1±1.29) and (2.05±0.92) respectively (P-Value=0.02, 95% C.I.), but when comparing the average actual weekly dose of Warfarin between the two groups it was found that there is no statistically significant difference (49.38±20.99 mg/week) and (48.45±14.22) respectively (P-Value=0.89, 95% C.I.). According to VKORC1 gene, it was found that there is no statistically significant difference in the average INR between patients who have homozygote or heterozygote VKORC1-1639A and that who have VKORC1(G/G) genotype (2.48±1.61) and (2.34±1.12) respectively (P-Value= 0.67, 95% C.I.), but there is a statistically significant difference in the average weekly dose between the two groups (40.36±14.04 mg/week) and (48.71±15.96 mg/week) respectively (P-Value=0.01, 95% C.I.). Also when averages of INR were compared between patients who have at least one copy of VKORC1-1639A allele and those who have CYP2C9*1/*1 and VKORC1(G/G), it was found that there is no statistically significant difference between the two means (2.4±1.23) and (2.05±0.92) respectively (P-Value=0.24, 95% C.I.), but there is a statistically significant difference in the average weekly dose of Warfarin between the two groups (40.63±14.13) and (48.45±14.22) respectively (P-Value=0.04, 95% C.I.). Conclusion: We conclude that the presence of at least one copy of CYP2C9*2 or VKORC1-1639A alleles or both is observed to be a cause for an increased sensitivity to Warfarin therapy and increased INR level. Therefore we recommend testing for these alleles as a part of the patient management
خطورة التنوع الجيني لدى مرضى السرطان في قطاع غزة
No full textLung cancer is a leading cause of cancer-related deaths throughout the world. Recent GWAS and consecutive validation supported that SNPs in the 15q25, 5p15.33 and 6p22 regions showed significant association with lung cancer risk in multiple populations. Therefore, in this study six SNPs in three genomic regions were investigated because of their already established involvement in different populations. The relationship between these SNPs and smoking has been investigated. Methods: The SNPs rs16969968, rs1051730, rs402710, rs2736100, rs9295740 and rs4324798 were genotyped in a case-control study with 30 cancer cases and 60 age- and gender-matched cancer-free controls, all from Palestinian population of Gaza strip. Whole blood samples were collected from all subjects and relevant personal and clinical data was also collected from the participants and/or their medical record. Gene polymorphisms at the specified SNPs were determined by allele specific PCR and RFLP-PCR methodology. Results: The SNP rs16969968 G>A allele and rs1051730 C>T allele were found significantly related to lung cancer risk (P-value = 0.022, OR= 3.23; 0.001, OR=3.05 respectively). The allelic frequencies for the susceptibility alleles of rs16969968 and rs1051730 were higher in the cases than in the controls (36.7% vs 23.3% and 46.7 vs 22.5% respectively). Homo- and heterozygote nicotine consuming individuals have higher rate of cigarettes consumption in case of rs16969968 G>A (40.0±15.81 and 36.04±12.2 CPD compared to the wild type P-Value=0.006), and in case of rs1051730 C>T (39.17±15.62 and 33.00±10.36 CPD P-Value=0.015). The rs402710 has significant relation with lung cancer susceptibility (P-Value =0.015, OR= 3.00) between cases and controls. However, No statistically significant differences could be found in the distribution of rs402710 SNP between smoker control and smoker cases (P-value = 0.621). In addition, rs402710 T allele can be considered as risk allele for NSCLC. The rs2736100 was also associated with risk of lung cancer (P=0.044, OR= 4.33) and the frequency of the risk allele between cases and controls was 35% vs 18.3% respectively. However, it didn’t have correlation with smoking quantity (P- value = 0.269). Also, the rs9295740 distribution for the risk allele among case (30.0%) and control (15.0%) is not statistically significant (P-value = 0.075), but between the smoker cases and smoker controls is statistically significant (P-value = 0.016), so it may be risk factor for lung cancer between smokers. The allele frequency for rs4324798 was 20% in controls and 0.0% in cases, so it may have a role in protection from lung cancer. Conclusion: Our findings provide further evidence supporting the genetic variants in 15q25, 5p15.33 and 6p22 regions associated with the risk of lung cancer. Smoking and lung infections are important triggers for lung cancer. Further studies with larger cohorts of Palestinian lung cancer patients are recommended to extend the outcomes of this study
معدل الانتشار و الفائدة الاكلينيكية لطفرة jak2 v617f بين مرضى اورام التكاثر النقبي في قطاع غزة
No full textBackground: Myeloproliferative neoplasms (MPNs) are a group of clonal hematopoietic stem cell malignancies. Classical Philadelphia negative MPNs comprise various disorders including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The JAK2 V617F mutation was identified among MPNs patients in 2005 using a variety of different methods. The discovery of activating point mutation JAK2 V617F provided a molecular basis for understanding the pathophysiology and development of Philadelphia negative MPNs and represents a diagnostic breakthrough for these disorders. Objectives: The aim of the present study was to investigate the prevalence and clinical utility of JAK2 V617F mutant allele among myeloproliferative neoplasms patients in Gaza strip. Methods: Peripheral blood samples were collected from 60 patients with Philadelphia negative MPNs (15 PV, 9 familial PV, 29 ET and 7 PMF) recruited from Hematology and Oncology Department and Outpatient Clinic of Al-Shifa Medical Complex. DNA was isolated from peripheral blood leukocytes and JAK2 V617F mutation was detected using allele specific polymerase chain reaction (AS-PCR). Laboratory parameters including CBC, serum iron profile, vitamin B12, folic acid and LDH were analyzed for all patients and their clinical data were obtained from patient’s medical records. Results: The overall prevalence of JAK2 V617F was 56.7% in MPNs, (86.7%) in PV, (0.0%) in familial PV, (62.1%) in ET and (42.9%) in PMF. The JAK2 V617F positivity was significantly correlated with higher WBCs count, RBCs count and HCT value in MPNs and with higher RBCs count and iron deficiency in PV and with higher RBCs and splenomegaly in ET. Other parameters such as age, gender disease duration, hemoglobin, platelets counts, serum ferritin, vitamin B12, folic acid, LDH and liver size did not show statistically significant differences between positive and negative JAK2 V617F in ET. When compared sporadic and familial PV patients according to clinical and laboratory parameters, age, RBCs count, MCV and platelets count showed statistically significant differences. During comparison of hematological and clinical parameters between male and female patients with JAK2 V617F mutation, the RBCs count, Hb, HCT, MCV and iron saturation exhibited statistically significant differences between JAK2 V617F positive and negative males. In addition, there were statistically significant differences in RBCs count, RDW and spleen size between females positive and negative for JAK2 V617F mutation. Conclusion: The prevalence of the JAK2 V617F mutation among the MPNs and their distinct subtypes comes in accordance with literature data and was found to be associated with iron deficiency among PV and with higher leukocyte and erythrocyte counts in MPNs in general. Screening for JAK2 V617F mutation should be incorporated into the initial evaluation of patients suspected to have MPNs, a conclusion that is supported by WHO recommended criteria
Prevalence and Risk Factors of Hepatitis B and C Viruses among Haemodialysis Patients in Gaza Strip, Palestine
Get PDFEnd stage renal disease patients (ESRD) on maintenance haemodialysis (HD) are at high risk of acquiring hepatitis B and C viruses (HBV, HCV) infection. The aim of this study is to investigate the prevalence of HBV and HCV infection and to determine risk factors associated with their transmission among HD patients in Gaza Strip. During the study all patients attending the four HD centers in Gaza Strip (246 patients) were tested for the presence of hepatitis B surface antigen (HBsAg) by using the second generation enzyme immunoassay and anti-HCV by using the third generation enzyme immunoassay. HCV RNA was detected using reverse transcriptase polymerase chain reaction (RT-PCR). A questionnaire that included possible risk factors was completed by the researcher via patient interview to insure proper data collection. The overall prevalence of HBV among the four HD centers was 8.1% compared with a prevalence rate of 2.3% among healthy blood donors inGazaaccording to the latest report of the Palestinian Ministry of Health (MOH). The main risk factors were HD center (p=0.05), history of blood transfusion (p<0.01) and treatment abroad (p=0.01). The overall prevalence of HCV among the four HD centers was 22% compared with a prevalence rate of 0.2% among healthy blood donors inGazaaccording to the latest report of MOH. The main risk factors were HD center (p<0.01), time duration on HD (p<0.01), history of blood transfusion (p<0.01), treatment abroad (p<0.01) and history of blood transfusion abroad (p<0.01). The much higher prevalence of Hepatitis viruses among HD patients compared to normal population of Gaza Strip indicates a causative relation between HD and hepatitis viruses transmission. Therefore extremely careful observation of preventive infection control measures is essential to limit Hepatitis viruses' transmission in HD centers
Expression of the Multiple Drug Resistance Associated Genes: MRP1, LRP and BCRP among Leukemia Patients in Gaza strip.
Get PDFHematological neoplasms are usually sensitive to chemotherapy, but with relatively high rate of relapse. Cell resistance to drugs is a major determinant of response to chemotherapy and its detection may be of clinical relevance. The role of expression of transmembrane carriers such as multidrug resistance related Protein 1 (MRP1), breast cancer resistance protein (BCRP) and lung resistance protein (LRP) genes in neoplastic cell survival and risk of relapse for leukemia patients was previously documented. Therefore, the aim of this study was to estimate the level of expression of MRP1, BCRP, and LRP genes in blood cells of leukemia patients inGazastrip by quantitative real-time RT-PCR technique, and to investigate any correlation between the expression of these genes and other previous and current clinical findings of the patient. Blood samples were collected from 70 leukemia patients (40 males and 30 females) admitted in the Hematology Departments of Al-Shefa hospital, the EuropeanGazaHospitaland AL-Nasser pediatric hospital in Gazastrip. The specimens were collected during the period between May to November, 2009. Patients’ medical data were obtained from their records in the relevant hospitals, and included personal, medical, management and family information (e.g. age, type of disease, severity of case, date of diagnosis of disease, types , protocols of treatments, prognosis, previous tests results and others). A control group of 35 normal healthy individuals was included mainly to correct for any inter-individual expression difference as a result of gender and age variation. This group was also used to compare the levels of gene expression in normal and leukemia patients. The level of expression of MRP1, LRP, and BCRP genes in cells of leukemia patients were quantitated by quantitative Real Time-PCR technique and normalized by the expression level of an endogenous control gene porphobilinogen deaminase (PBGD). The SPSS version 15 was used for statistical analysis. Five types of leukemia, from different areas ofGazastrip, were included in this study. Thirty cases (42.9%) were acute lymphoblastic leukemia, 5 cases (7.1%) acute myeloblastic leukemia, 12 cases (17.1%) chronic lymphoblastic leukemia, 22 cases (31.4%) chronic myeloblastic leukemia and 1 case (1.4%) small lymphoblastic leukemia. The mean age of cases was 32.9 ±28.2 years and the mean age of controls was 27.2 ±18.8 years. MRP1 and LRP but not BCRP mean level of gene expression was significantly higher in leukemia group than normal control group. MRP1 gene expression in ALL patients was lower than all types of leukemia and significantly lower than in AML (P=0.001). LRP gene expression was significantly higher in AML and CML patients than in control group (AML: P=0.021 and CML: P=0.001). LRP gene expression in ALL patients were significantly lower than CML patients (P=0.024); and in CML patients higher than CLL patients (P=0.046). There was no statistically significant difference between leukemia types in BCRP gene expression levels. MRP1 and LRP mean levels of expression in remission was less than with no remission patients and this decrease of expression was statistically significant (MRP1: P=0.003 & LRP: P=0.050). The mean level of BCRP gene expression in remission patients was also less but with no statistical significance. When comparing the level of MRP1, LRP and BCRP according to management protocols and gender of patient no significant relationship was established. The outcome of the current study indicates that higher levels of MRP1, LRP and BCRP expression are correlated with chemotherapeutic treatment failure of leukemia patients. Therefore we suggest these factors to be included in the design and application of chemotherapy protocols in Gaza Strip
Prevalence of Mycoplasma gallisepticum in the Ten licensed Hatcheries in Gaza strip, Palestine
Get PDFAvian mycoplasmas are pathogens of different avian species, especially poultry. MG is the most important mycoplasma. Vertical transmission can occur in eggs laid by naturally infected hens or horizontally within the hatcheries resulting in rapid spread of the disease throughout the flock. It is common in many parts of the world as the primary agent of chronic respiratory disease and sinusitis causing important economic losses in the poultry industry and increase the risk to the overall health of human. The study was conducted in ten licensed local hatcheries, which hatch more than 16 million of one old day chicks yearly for more than 1200 poultry breeding farms inGazastrip governorates. The study aimed to determine the prevalence of MG infection in representative samples of 390 non-incubated imported fertilized eggs collected systematically randomly in August 2010 fromGazastrip hatcheries. In addition, the diagnostic value of rapid slide agglutination (RSA) test and real time polymerase chain reaction (real time PCR) technique was compared and the current control procedure was investigated. The results showed that the prevalence of MG specific antibodies by using RSA test was (36.6%) while the prevalence of MG-DNA by using real time PCR technique was (6.2%). In addition, the imported eggs, which were used for hatching process, were not handled in the best-case specifications and quality control measures were limited or absent. A significant correlation between the eggs weight and the prevalence of MG specific antibodies and between the eggs weight and the prevalence of MG-DNA were found. The poultry industry inGazastrip is facing the infection of MG in the imported fertilized eggs, and the visual observation and certification assessment are not enough for prevention of MG transmission. The free MG egg sources, bio-safety measures, knowledge and protection programs could be reduce the rate of infection
Determination of Hepatitis C Virus Genotypes in Gaza Strip
Get PDFHepatitis C virus is a heterogeneous virus with 6 major genotypes and more than 50 subtypes. The present work aims to determine the commonest HCV genotypes in chronic patients ofGazastrip,Palestine. This study highlights the prognostic potential of determining the HCV genotype for patients as an integral part of their diagnostic and therapeutic regimen, and thus may be helpful in tailoring the therapy for HCV patients based on their virus genotype. If taken in conjunction with other factors important in therapy HCV genotyping will reduce the expenses of treatment when the duration of therapy is accordingly optimized, and thus allowing a larger number of patients to be considered for the therapy. Genotyping of HCV may also be useful for identifying some important origins of transmission and risk factors of the virus inGazastrip. The chronic HCV patients participating in the study were interviewed, and a questionnaire was completed and serum samples were obtained from each of them. The samples were analyzed to justify the presence of HCV RNA by reverse transcriptase polymerase chain reaction (RT/PCR), and the PCR products of 92 positive samples were purified and submitted for sequencing and genotype determination. ALT level was determined for each sample. The results of this study showed that genotype 1 and 4 and their subtypes 1a, 1b, 4a and 4c/d are the major common HCV genotypes in Gaza strip. Genotype 4 and its subtypes are the predominant ones. Genotype 1 and its subtypes collectively contributed to 28.3% of the cases, while genotype 4 and its subtypes collectively contributed to 64.1% of the cases. Mixed infection with the two genotypes was also seen among 7.6% of the cases. Travelling, surgery and blood transfusion in an endemic HCV area are the major roots of HCV transmission inGazastrip although other routs exist. The results also show that genotype 1 infections are more serious than genotype 4 infections and associated with significantly higher ALT levels in patients' blood. The education level, infection date and hemodialysis don’t show any significant relation to the HCV genotype and subtypes. The results of this study contribute to the identification of sources of outbreaks, risk factors and control strategy of HCV. The results will also help tailor treatment schedules as well as to monitor response to antiviral treatment
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