IKZF1 rs4132601 and rs11978267 gene polymorphisms and paediatric systemic lupus erythematosus; relation to lupus nephritis.

The demographic factors, the socioeconomic status and the ethnicity of populations are important players that determine the incidence, the prevalence and the spectrum of systemic lupus erythematosus (SLE) clinical presentations in different populations. Therefore, the purpose of the present research was to investigate the possible association between the Ikaros family zinc finger 1 gene (IKZF1) rs4132601 and rs11978267 single nucleotide polymorphisms (SNPs) and SLE susceptibility and clinical presentations including lupus nephritis (LN) among Egyptian paediatric patients. After DNA extraction from Ethylenediaminetetraacetic acid (EDTA) blood samples for 104 paediatric SLE (pSLE) patients and 286 healthy controls, the investigated SNPs (IKZF1 rs4132601 and rs11978267) were genotyped using TaqMan-Real-time Polymerase chain reaction (PCR). The G allele, GG and GT genotypes of IKZF1 rs4132601 were associated with pSLE (pc<.001, OR 2.97, 3.2 and 2.25, respectively). The GG and GA haplotype were more frequent in pSLE patients than other haplotypes (pc<.001, OR 3.47 and pc = .004, OR = 2.8, respectively). The studied SNPs have no impact on the distinctive features of pSLE. The rs4132601 TG genotype was significantly associated with proliferative LN (pc = .03) The IKZF1 rs4132601 can be considered a risk factor for SLE in the cohort of Egyptian children. The TG genotype of the IKZF1 rs4132601 may predispose to proliferative LN.

Exploiting Signal Joint T Cell Receptor Excision Circle to Investigate the Impact of COVID-19 and Autoimmune Diseases on Age Prediction and Immunosenescence.

Signal joint T cell receptor excision circles (sjTRECs) are a promising marker for age estimation and immunosenescence in different ethnic groups. Several limitations are expected to overshadow their use as accurate markers for age prediction. The current study was conducted to determine the influence of immunologic disorders, such as autoimmune diseases and COVID-19, on the accuracy of sjTRECs as molecular markers for age estimation and immunosenescence among living Egyptians. Peripheral blood sjTRECs level was measured by qPCR in 90 autoimmune patients, 58 COVID-19 patients, and 85 healthy controls. The mean dCt values were significantly (p = 0.0002) different between the three groups, with the highest values in healthy subjects, followed by autoimmune and COVID-19 patients. A significant negative correlation was identified between the sjTRECs levels and ages in all studied cases. There were significant positive correlations between chronological age and predicted age for healthy individuals, autoimmune, and COVID-19 patients with mean absolute deviations (MAD) of 9.40, 11.04, and 9.71, respectively. The two patients' groups exhibited early immunosenescence, which was more noticeable among the young adults with COVID-19 and autoimmune patients of age range (18-49 years). Autoimmunity may represent a critical factor impacting the accuracy of sjTRECs quantitation for age prediction.

Anti-vinculin antibodies as a novel biomarker in Egyptian patients with systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune disorder that causes vasculopathy and scarring, most commonly in the lungs and skin, but it can also affect other organs. Endothelial vinculin plays a critical role in angiogenesis regulation. Therefore, vinculin overexpression in SSc may give rise to anti-vinculin antibodies, which may contribute to the development of SSc vasculopathy. The current research aims to (1) determine whether anti-vinculin autoantibodies play a significant role in the diagnosis of SSc and (2) compare anti-vinculin serum levels between two scleroderma patient populations, namely, pulmonary artery hypertension (PAH)-predominant and interstitial pulmonary fibrosis (IPF)-predominant groups. METHODS: This research included 140 participants categorized into three groups: group I-patients with PAH-predominant; group II-patients with ILD-predominant; group III-the control group. Anti-vinculin antibodies were detected in serum samples collected from all participants using ELISA. All subjects underwent high-resolution computed tomography (CT), diffusing capacity for carbon monoxide, and pulmonary function tests. RESULTS: Patients in group I (PAH-predominant group, N = 35) were 41.3 [± 11.4] years old, with 80% being women. Patients in group II (ILD-predominant group, N = 35) were 41.0 [± 11.5] years old. The SSc group showed significantly higher anti-vinculin antibody levels than the control group (P < 0.001). The PAH-predominant group demonstrated significantly higher anti-vinculin antibody levels and anti-vinculin positivity than the ILD-predominant group. CONCLUSION: Anti-vinculin antibodies in the blood appear to be diagnostic biomarkers for scleroderma. Furthermore, they shed light on some novel perspectives on the pathophysiology of specific lung fibrotic changes. Key Points • This study included two groups of systemic sclerosis patients (PAH-predominant group, ILD-predominant group) as well as a control group to investigate the significance of anti-vinculin antibodies in such cases. • Our results have demonstrated that anti-vinculin antibodies can play a significant role in diagnosing and monitoring systemic sclerosis disease.

ARID5B rs10821936 and rs10994982 gene polymorphism and susceptibility to juvenile systemic lupus erythematosus and lupus nephritis.

BACKGROUND: The prevalence of SLE and the spectrum of clinical manifestations vary widely in different races and geographical populations. OBJECTIVE: To investigate the possible role of ARID5B rs10821936 and rs10994982 polymorphism as a risk factor for the development of SLE in children (jSLE) and to evaluate their role in relation to clinical manifestations especially lupus nephritis (LN). METHODS: DNA extraction and Real-time PCR genotyping of ARID5B rs10821936 and rs10994982 were done for 104 jSLE and 282 healthy controls. RESULTS: The C allele and C containing genotypes (CC, CT and CC+CT) of ARID5B rs10821936 were higher in children with SLE (p = 0.009, OR = 1.56, 0.037, OR = 2.35, 0.016, OR = 1.81 and 0.008 OR = 1.88 respectively). ARID5B rs10994982 alleles, genotypes and haplotypes are not associated with jSLE (p > 0.05). The ARID5B rs10821936 and rs10994982 genotypes showed non-significant associations with LN, proliferative versus non proliferative and biopsy grades (p > 0.05). CONCLUSION: ARID5B rs10821936 SNP may be a susceptibility risk factor for juvenile SLE in the studied cohort of Egyptian children.

IKZF1 rs4132601 and rs11978267 Gene Polymorphisms and Acute Lymphoblastic Leukemia: Relation to Disease Susceptibility and Outcome.

(IKZF1) rs4132601 and rs11978267 are common gene polymorphisms and have been associated with the risk of acute lymphoblastic leukemia. However, these associations are less evident in races and/or ethnicities other than European and Hispanic. Therefore, we investigated the association between these single-nucleotide polymorphisms and acute lymphoblastic leukemia susceptibility and disease outcome. Real-time polymerase chain reaction typing was performed for IKZF1 rs4132601 and rs11978267 for 128 pediatric acute lymphoblastic leukemia (pALL), 45 adult acute lymphoblastic leukemia (aALL), and 436 healthy controls. The G allele-containing and G-containing genotypes (GG+GT) of rs4132601 were significantly higher in pALL (P=0.003, odds ratio [OR]=1.65, 0.009, OR=1.42, respectively) and aALL (P=0.016, OR=1.81 and 0.011, OR=1.61, respectively). However, the GG haplotype was associated with the risk of pALL (P=0.044), the GA haplotype was associated with the risk of aALL (P=0.007). In aALL, the GG genotype of rs4132601 was associated with absence of remission and poor overall survival (P=0.003 and 0.041, respectively). The IKZF1 rs4132601 single-nucleotide polymorphism can be considered a susceptibility risk factor for the development of pALL and aALL in the studied cohort of Egyptian patients. The GG genotype of IKZF1 rs4132601 may be a risk factor for poor outcome in aALL patients.

ARID5B rs10821936 and rs10994982 gene polymorphisms and acute lymphoblastic leukemia: relation to disease susceptibility and outcome.

ARID5B rs10821936 and rs10994982 single nucleotide polymorphism (SNP) have been associated with the risk of acute lymphoblastic leukemia (ALL) in different ethnic populations. We investigated the association between the ARID5B rs10821936 C > T, rs10994982 A > G, and susceptibility to ALL in a cohort of Egyptian individuals and investigated their role in relation to disease outcome. Real-time PCR typing was done for ARID5B rs10821936 and rs10994982 SNPs for 128 pediatric ALL (pALL), 45 adult ALL (aALL), and 436 healthy controls. Significant risk associations were found between the C allele (p < 0.001, OR = 2.02), CC genotype (p < 0.001, OR = 2.72), CT genotype (p = 0.011, OR = 1.45) of ARID5B rs10821936 and pediatric ALL especially T-ALL and adult ALL (p < 0.05). The CA haplotype (C allele of rs10821936 + A allele of rs10994982) was associated with the risk of ALL either pediatric ALL or adult ALL (p < 0.001). In the studied Egyptian population, it can be concluded that the C allele, CC, and CT genotypes of ARID5B rs10821936 and the CA haplotype may be a susceptibility risk factor for pediatric and adult ALL. However, the SNPs of ARID5B rs10821936 and rs10994982 were not found to be strongly associated with ALL outcomes.

Evaluation of vitamin D receptor gene polymorphisms (Fok-I and Bsm-I) in T1DM Saudi children.

BACKGROUND: Vitamin D deficiency conferred strongest susceptibility to pathogenesis of type 1 diabetes mellitus (T1DM). Altered gene expression and function have strong effect on VDR gene polymorphism. OBJECTIVES: We aimed to check for the association of two single nucleotide polymorphisms (SNPs) in VDR gene (Fok-I and Bsm-I) with T1DM in Saudi children. SUBJECTS AND METHODS: Cross-sectional study included 100 T1DM Saudi children, plus 102 unrelated healthy subjects. PCR technique was used for detection of Fok-I and Bsm-I SNPs in VDR gene. RESULTS: Regarding the Fok-I polymorphisms, T1DM cases showed a significant increased frequency of the heterozygous genotype (Ff) than controls (33% vs 21%, OR = 1.9, 95% CI = 1.006-3.587, P = .04). In the meantime, they showed significantly lower frequency of the homozygous (ff) genotype (64% vs 79%, OR = 0.51, 95% CI = 0.28-0.96, P = .03). Cases showed also a significantly lower frequency of the (f) allele than controls (80.5% vs 87.7%, OR = 0.57, 95% CI = 0.33-0.995, P = .04). On the other hand, cases showed significantly higher frequency of the Bsm-I homozygous (bb) and heterozygous (Bb) genotypes (25% vs 11.8%, P = .01, OR = 2.5, 95% CI = 1.18-5.31) & (45% vs 27.5%, P = .0, OR = 2.1, 95 % CI = 1.20-3.89, respectively). Cases showed also significantly higher frequency of (b) allele compared to control (47.5% vs 25.5%, P = .0, OR = 2.6, 95% CI = 1.74-4.02). Haplotype analysis showed an increased risk with the fB and fb haplotypes. CONCLUSION: This study emphasizes a positive association between SNPs (Fok-I and Bsm-I) and T1DM among Saudi children with increased risk with the Fok-I F and Bsm-I b alleles.

Tuberculosis/toxoplasmosis co-infection in Egyptian patients: A reciprocal impact.

OBJECTIVE: To assess the concurrent toxoplasmosis infection in Egyptian TB patients and the impact of each infection on the other in terms of increased severity of TB or reactivation of latent Toxoplasma infection. METHODS: Three hundred suspected pulmonary TB cases were initially screened for TB using direct Ziehl Neelsen staining and Lowenstein Jensen culture of their sputa. Rifampicin resistance was detected by Xpert MTB/RIF assay. Control group of 30 age and sex-matched healthy individuals negative for TB was included for comparison. All subjects were further assessed for serum levels of anti-Toxoplasma IgG antibodies and malondialdehyde (MDA). RESULTS: Forty three confirmed TB-infected patients including 10 (23.3%) rifampicin-resistant patients were detected. Associated toxoplasmosis was found to be significantly higher among TB patients (OR = 2.709; 95% CI: 1.034-7.099; P<0.05) and among rifampicin sensitive than rifampicin resistant TB patients (OR=0.213; 95% CI: 0.048-0.951; P < 0.05). Serum levels of anti-Toxoplasma IgG antibodies and MDA were significantly higher among TB patients than the control group. Furthermore, serum level of MDA was significantly higher among TB/Toxoplasma co-infected patients as compared to toxoplasmosis free-TB patients. Strong positive correlation was detected between serum levels of anti-Toxoplasma IgG and MDA in TB patients (r = 0.75, P = 0.001). CONCLUSIONS: Among pulmonary TB Egyptian patients, there is a considerable prevalence of toxoplasmosis. Severity of pulmonary tuberculosis could be increased by Toxoplasma co-infection.

GATA3 rs3824662 gene polymorphism as possible risk factor in a cohort of Egyptian patients with pediatric acute lymphoblastic leukemia and its prognostic impact.

To investigate the possible role of GATA3 rs3824662 polymorphism as risk factor for the development of acute lymphoblastic leukemia (ALL) in a cohort of Egyptian children and to evaluate its prognostic role. Typing of GATA3 rs3824662 polymorphism was done using real-time PCR for 116 patients with ALL and 273 healthy controls. The A allele and AA genotype were significantly higher in ALL patients (p = .015 and .016, respectively) especially B-ALL (p = .014 and .01, respectively). The AA genotype was associated with shorter disease free survival (DFS) in univariate (p = .017) and multivariate cox regression analysis (p = .028), increased incidence of relapse (p = .008) and poor prognosis (p = .028) in pediatric ALL. The GATA3 rs3824662 A allele and AA genotype may be risk factors for the development of pediatric ALL especially B-ALL in the studied cohort of Egyptian patients. The AA genotype is associated with shorter DSF, increased incidence of relapse and poor prognosis in pediatric ALL.

Interleukin-17A rs2275913, Interleukin-17F rs763780 and rs2397084 gene polymorphisms as possible risk factors in Juvenile lupus and lupus related nephritis.

UNLABELLED: There are no reports about the association of interleukin (IL)-17A and IL-17F gene polymorphism and susceptibility to pediatric systemic lupus erythematosus (pSLE). OBJECTIVE: To examine the possible role of IL-17A rs2275913, IL-17F rs763780 and rs2397084 polymorphisms as risk factors for pSLE in a cohort of Egyptian children and to investigate their association with the clinico-pathological features including lupus nephritis (LN). METHODS: Typing of IL-17A and IL-17F polymorphisms was done using restriction fragment length polymorphism for 115 children with SLE and 259 age- and sex-matched healthy controls. RESULTS: No significant differences were found between pSLE patients and healthy controls for the allele and genotype frequencies of IL-17A rs2275913, IL-17F rs763780 and rs2397084 (p > 0.05). However, the combined genotype GGAGAA and the haplotype GGA had significant association with pSLE (pc = 0.042 and <0.001, respectively). The AA genotype of IL-17F rs763780 is more frequent in female patients (p = 0.002) and the AA genotype of IL-17F rs2397084 is more associated with positivity of ds-DNA (p = 0.007). No more associations were found for the demographic and clinical data of pSLE patients including risk of LN development, risk of non-remission, overall survival, activity and chronicity indices. CONCLUSION: The GGAGAA combined genotype and the GGA haplotype of IL-17A rs2275913, IL-17F rs763780 and rs2397084 can be considered risk factors for the development of SLE in Egyptian children. IL-17A rs2275913, IL-17F rs763780 and rs2397084 are not related to the LN development, SLE disease activity or overall survival.

Relation of interleukin-10 Promoter Polymorphisms to Adult Chronic Immune Thrombocytopenic Purpura in a Cohort of Egyptian Population.

BACKGROUND: Adult chronic immune thrombocytopenic purpura (chronic ITP) is an autoimmune multifactorial bleeding disorder that occurs because of enhanced peripheral platelet destruction. Treatment decisions can be challenging because the goal of treatment is to prevent severe bleeding, but the risk of bleeding can be difficult to estimate for any individual patient. OBJECTIVE: This case-control study was planned to investigate the relationship of interleukin (IL)-10 promoter (IL-10-1082, -819 and -592) polymorphisms with the susceptibility, severity and outcome of adult chronic ITP in a cohort of Egyptian population. SUBJECTS AND METHODS: Typing of IL-10 promoter polymorphisms was done using restriction fragment length polymorphism for 62 adult patients with chronic ITP and 73 age- and sex-matched healthy controls. RESULTS: No significant differences were found between ITP patients and controls regarding the frequency of IL-10 promoter genotypes, alleles or haplotypes. IL-10-592 AA genotype and ATA (IL-10-1082, -819 and -592) haplotype were associated with severe ITP (p = 0.003, 0.043, respectively). CONCLUSION: Our findings suggest that the IL-10 promoter polymorphisms are unlikely to affect the development or treatment outcome of chronic adult ITP in Egyptian population, but IL-10-592 AA genotype and IL-10 (-1082, -819 and -592) ATA haplotype may be associated with disease severity. Because ITP is a complex disease, it is recommended that a multicenter study should be done with large sample size and unified typing technique.

Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and susceptibility to acute lymphoblastic leukemia in a cohort of Egyptian children.

This case-control study was planned to investigate the possible role of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as a risk factor for the development of acute lymphoblastic leukemia (ALL) in a cohort of Egyptian children. Typing of MTHFR C677T and A1298C polymorphisms was done using restriction fragment length polymorphism (RFLP) for 100 children with ALL and 100 age- and sex-matched healthy controls. No significant differences were found between patients with ALL and controls for the frequency of MTHFR C677T and A1298C alleles, genotypes, combined genotypes or haplotypes. The C677T and A1298C genotype frequency was different from that in Korean and Chinese populations (p < 0.5) and was similar to that in British, French-Canadian and German-Caucasian populations (p > 0.5). Our findings suggest that MTHFR C677T and A1298C polymorphisms are unlikely to affect the development of childhood ALL in an Egyptian population from Delta.

BMI1 gene expression in myeloid leukemias and its impact on prognosis.

BACKGROUND: BMI1 is a polycomb group (PcG) protein and is overexpressed in leukemia. It plays a key role in the self-renewal of stem cells. Leukemic cells lacking BMI1 underwent proliferation arrest and showed signs of differentiation and apoptosis. AIM: This study was aimed to investigate the expression and impact of BMI1 in myeloid leukemias. Expression levels of BMI1 in 100 acute myeloid leukemia (AML), 100 chronic myeloid leukemia (CML) patients and 20 healthy controls were measured by real time quantitative polymerase chain reaction (RQ-PCR). RESULTS: The results showed that the expression of BMI1 was significantly higher in AML and CML versus control subjects (p<0.001 for both). The 2-year overall and disease free survival rates were significantly lower in patients expressing higher BMI1. Multivariate analysis showed that BMI1 was independent prognostic factor for OS for AML cases (p=0.015, HR=3.204, 95% CI=1.250-8.212). Accelerated and blastic phases in CML cases expressed higher BMI1 than chronic phase (p<0.001). CONCLUSION: We concluded that detecting BMI1 is helpful for predicting the survival in AML patients and monitoring the aggressiveness and progression in patients with CML.

Donor rejection before living donor liver transplantation: causes and cost effective analysis in an egyptian transplant center.

BACKGROUND: In the living donor liver transplant setting, the preoperative assessment of potential donors is important to ensure the donor safety. OBJECTIVES: The aim of this study was to identify causes and costs of living liver-donors rejection in the donation process. MATERIALS AND METHODS: From June 2010 to June 2012, all potential living liver donors for 66 liver transplant candidates were screened at the Ain Shams Center for Organ Transplantation. Potential donors were evaluated in 3 phases, and their data were reviewed to determine the causes and at which phase the donors were rejected. RESULTS: One hundred and ninety two potential living liver donors, including 157 (81.7%) males, were screened for 66 potential recipients. Of these, 126 (65.6%) were disqualified for the donation. The causes of rejection were classified as surgical (9.5 %) or medical (90.5 %). Five donors (3.9 %) were rejected due to multiple causes. Factor V Leiden mutation was detected in 29 (23 %) rejected donors (P = 0.001), 25 (19.8 %) donors had positive results for hepatitis serology (P = 0.005), and 16 (12.7 %) tested positive for drug abuse. Portal vein trifurcation (n = 9, 7.1%) and small size liver graft estimated by CT volumetric analysis (n = 6, 4.8 %) were the main surgical causes which precluded the donation. CONCLUSIONS: Among potential Egyptian living liver donors, Factor V Leiden mutation was a significant cause for live donor rejection. A stepwise approach to donor assessment was found to be cost-effective.

CEBPA gene mutations in Egyptian acute myeloid leukemia patients: impact on prognosis.

AIM: To assess the prognostic role of myeloid transcription factor gene CEBPA (CCAAT/enhancer binding protein-α), a novel gene involved in leukemia in Egyptian adults AML. MATERIALS AND METHODS: Screening for CEBPA mutations was assessed using PCR-single-strand conformation polymorphism (PCR-SSCP) in pretreatment bone marrow samples from 55 newly diagnosed adult AML. RESULTS: CEBPA mutations were found in 11 (20%) of 55 AML patients. They had significantly higher hemoglobin (P = 0.037), and lower LDH (P = 0.003) levels when compared to those without. CEBPA mutations were frequently detected in M4 (45.5%) and M2 (27.2%) subtypes, and significantly associated with normal karyotype (90.9%, P = 0.007). We distinguished six cases with two different mutations or one homozygous mutation (CEBPA(double-mut)) as well as five cases with only one single heterozygous mutation (CEBPA(single-mut)). Patients with CEBPA mutations had significantly higher complete remission (P = 0.047), lower mortality (p = 0.047). Double CEBPA mutant cases showed longer disease free survival (DFS) and overall survival (OS) when compared to wild type CEBPA (for DFS; median = 27 versus 24 months respectively; P = 0.009 and for OS; median = 28 versus 25 months respectively; p = 0.008). No significant differences were found between CEBPA(single-mut) cases and wild type cases regarding DFS and OS (for DFS; median = 13 versus 24 months respectively; P = 0.615 and for OS; median = 14 versus 25 months respectively; P = 0.703). CONCLUSION: CEBPA mutation status is known to be a prognostic factor for favorable outcome in AML patients. CEBPA(double-mut) is associated with favorable DFS and OS. In contrast, CEBPA(single-mut) AMLs survival studies did not differ significantly with wild-type cases. These results demonstrate significant underlying heterogeneity within CEBPA mutation positive AML with prognostic relevance. Based on these findings, we propose that CEBPA(double-mut) should be clearly defined from CEBPA(single-mut) AML and considered as a separate entity in the classification of AML. Furthermore, incorporation of CEBPA mutation status into novel risk-adapted therapeutic strategies in Egypt will improve the currently disappointing cure rate of this group of patients.