Autoimmune Regulator Gene Polymorphisms and the Risk of Primary Immune Thrombocytopenic Purpura: A Case-Control Study.

This study aimed to assess the possible association between two single nucleotide polymorphisms (SNPs) of the autoimmune regulator (AIRE) gene (rs2075876 G/A and rs760426 A/G) with the risk of primary immune thrombocytopenia (ITP), as well as AIRE serum levels, in the Egyptian population. In this case-control study, 96 cases with primary ITP and 100 healthy subjects were included. Two SNPs of the AIRE gene (rs2075876 G/A and rs760426 A/G) were genotyped via Taqman allele discrimination real-time polymerase chain reaction (PCR). Additionally, serum AIRE levels were measured using the enzyme-linked immunosorbent assay (ELISA) technique. After adjusting for age, gender, and family history of ITP, the AIRE rs2075876 AA genotype and A allele were associated with increased ITP risk (adjusted odds ratio (aOR): 4.299, p = 0.008; aOR: 1.847, p = 0.004, respectively). Furthermore, there was no significant association between AIRE rs760426 A/G different genetic models and ITP risk. A linkage disequilibrium revealed that A-A haplotypes were associated with an increased ITP risk (aOR: 1.821, p = 0.020). Serum AIRE levels were found to be significantly lower in the ITP group, positively correlated with platelet counts, and were even lower in the AIRE rs2075876 AA genotype and A allele, as well as A-G and A-A haplotype carriers (all p < 0.001). The AIRE rs2075876 genetic variants (AA genotype and A allele) and A-A haplotype are associated with an increased ITP risk in the Egyptian population and lower serum AIRE levels, whereas the SNP rs760426 A/G is not.

The Impact of SKP2 Gene Expression in Chronic Myeloid Leukemia.

Introduction: The prognosis of chronic myeloid leukemia (CML) patients has been dramatically improved with the introduction of imatinib (IM), the first tyrosine kinase inhibitor (TKI). TKI resistance is a serious problem in IM-based therapy. The human S-phase kinase-associated protein 2 (SKP2) gene may play an essential role in the genesis and progression of CML. Aim of the study: We try to explore the diagnostic/prognostic impact of SKP2 gene expression to predict treatment response in first-line IM-treated CML patients at an early response stage. Patients and methods: The gene expression and protein levels of SKP2 were determined using quantitative RT-PCR and ELISA in 100 newly diagnosed CML patients and 100 healthy subjects. Results: SKP2 gene expression and SKP2 protein levels were significantly upregulated in CML patients compared to the control group. The receiver operating characteristic (ROC) analysis for the SKP2 gene expression level, which that differentiated the CML patients from the healthy subjects, yielded a sensitivity of 86.0% and a specificity of 82.0%, with an area under the curve (AUC) of 0.958 (p < 0.001). The ROC analysis for the SKP2 gene expression level, which differentiated optimally from the warning/failure responses, yielded a sensitivity of 70.59% and a specificity of 71.21%, with an AUC of 0.815 (p < 0.001). Conclusion: The SKP2 gene could be an additional diagnostic and an independent prognostic marker for predicting treatment responses in first-line IM-treated CML patients at an early time point (3 months).

CCL2 rs1024611Gene Polymorphism in Philadelphia-Negative Myeloproliferative Neoplasms.

Introduction: The onset of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) is caused by acquired somatic mutations in target myeloid genes "driver mutations". The CCL2 gene is overexpressed by non-Hodgkin lymphomas and multiple solid tumors. Aim of the study: to evaluate the possible association of CCL2 rs1024611 SNP and its expression level and the risk of developing Philadelphia-negative MPNs. Patients and methods: A total of 128 newly diagnosed Philadelphia-negative MPN patient and 141 healthy subjects were evaluated for the genotype distribution of CCL2 rs1024611 and CCL2 expression levels. Results: The CCL2 rs1024611 G/G genotype was more frequent and significantly frequent among PMF and Post-PV/ET-MF patients and the mean CCL2 expression levels were significantly higher in PMF and Post-PV/ET-MF compared to the healthy subjects. The CCL2 rs1024611 SNP was significantly correlated to the CCL2 gene expression level and fibrosis grade. ROC analysis for the CCL2 gene expression level that discriminates MF patients from PV + ET patients revealed a sensitivity of 80.43% and a specificity of 73.17% with an AUC of 0.919 (p < 0.001). Conclusion: The CCL2 rs1024611 polymorphism could be an independent risk factor for developing MF (PMF and Post-PV/ET-MF). Moreover, CCL2 gene expression could be potential genetic biomarker of fibrotic progression.

Genetic Risk Profiling Associated with Recurrent Unprovoked Venous Thromboembolism.

INTRODUCTION: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and/or pulmonary embolism (PE), is a common, acute, multifactorial disease with a five-years cumulative incidence of recurrence of approximately 25%. Actually, no single genetic defect can predict the risk of recurrence of VTE. Therefore, individual genetic risk profiling could be useful for the prediction of VTE recurrence. AIM OF THE STUDY: To assess the combined effect of the common prothrombotic genotypes on the risk of recurrence of VTE in recently diagnosed unprovoked VTE patients. PATIENTS AND METHODS: This population based, prospective follow-up study was carried out from January 2015 to December 2020 in (internal medicine, cardiovascular medicine and anesthesia and ICU departments, Tanta University Hospital, Egypt) on 224 recently diagnosed unprovoked VTE patients. Whole blood was collected by standard venipuncture at the time of admission prior to the beginning of anticoagulant therapy. Genomic DNA was extracted and was genotyped for the 5-SNPs Genetic risk score (GRS), previously validated for first venous thrombosis (FVL rs6025, PTM rs1799963, ABO rs8176719, FGG rs2066865 and FXI rs2036914). RESULTS: The main important finding in the present study was that patients having ≥3 risk alleles were associated with higher risk of VTE recurrence compared to those having ≤2 risk alleles (the reference group) (HR 2.5, 95% CI 1.48-4.21) (p = 0.001). Patients with GRS ≥ 3 had a significantly shorter time recurrence free survival (43.07 months) compared to the low risk group of patients with GRS (0-2) (p < 0.001). CONCLUSION: GRS model could be an effective and useful model in risk stratification of VTE patients, and genetic risk profiling of VTE patients could be used for the prediction of recurrence of VTE.

Diagnostic efficacy of serum and urinary netrin-1 in the early detection of diabetic nephropathy.

This study aimed to assess the diagnostic value of serum and urinary netrin-1 in patients with type 2 diabetes mellitus (T2DM) at different stages of diabetic nephropathy (DN) and to compare its efficacy of estimation in serum with that in the urine. This study was carried out on 135 patients with T2DM and 45 healthy subjects. The patients with diabetes were divided according to urinary albumin creatinine ratio (UACR) into: T2DM with normoalbuminuria, incipient DN with microalbuminuria, and overt DN with macroalbuminuria groups. Serum and urinary levels of netrin-1 were measured by ELISA. The mean levels of serum and urinary netrin-1 were significantly higher in the microalbuminuric and macroalbuminuric patients with DN than those in the normoalbuminuric patients with T2DM, with the highest values detected in macroalbuminuric patients with DN. Urinary netrin-1 level was significantly higher in the normoalbuminuric T2DM group than control group, whereas no significant difference existed regarding serum netrin-1 level. In T2DM groups, the urinary and serum netrin-1 correlated with each other and were independently related to fasting blood glucose, UACR, and estimated glomerular filtration rate. Receiver operating characteristic curve analysis showed that the area under the curve of urinary netrin-1 was 0.916 which is significantly higher than that of serum netrin-1 (0.812) for the detection of incipient DN and reached 0.938 on coestimation of both urinary and serum netrin-1. In conclusion, netrin-1 is a potential diagnostic marker for early detection of DN with its estimation in urine has higher accuracy than that of serum.

Role of serum Metadherin mRNA expression in the diagnosis and prediction of survival in patients with colorectal cancer.

Early diagnosis and treatment of colorectal cancer (CRC) are important for improving patients' survival. Metadherin is an oncogene that plays a pivotal role in carcinogenesis and can be suggested as a cancer biomarker. This study aimed to elucidate the efficacy of serum Metadherin mRNA expression as a potential non-invasive biomarker for early diagnosis of CRC in relation to other screening markers as carcinoembryonic antigen (CEA), carbohydrate antigen 19.9 (CA19.9) and Fecal occult blood (FOB) and also to assess its relationship with the tumor stage and survival rate. A convenience series of 86 CRC cases (group I) were recruited with 78 subjects as controls (group II). Serum Metadherin mRNA expression level was determined using reverse transcription polymerase chain reaction (RT-PCR). Serum Metadherin mRNA expression level was significantly elevated in CRC cases when compared with controls (P < 0.001). For CRC diagnosis; Receiver operator characteristic (ROC) analyses revealed that the diagnostic accuracy of serum Metadherin mRNA (AUC = 0.976) was significantly higher than other routine CRC screening markers as CEA, CA19.9 and FOB. The combined accuracy of these markers (AUC = 0.741) was increased when used with serum Metadherin mRNA (AUC = 0.820). High serum Metadherin mRNA expression was associated with poorly differentiated histological grade, advanced tumor stage and lower survival rate. AUC of Metadherin was 0.820 for differentiating advanced versus early tumor stages. Serum Metadherin mRNA expression is a useful non-invasive biomarker for CRC. It can be used for screening and early diagnosis of CRC and can increase the efficacy of other routine CRC screening markers when it is estimated in CRC patients with them. It is also associated with advanced tumor stage and a lower survival rate.

Impact of CD40 gene polymorphisms on the risk of immune thrombocytopenic purpura.

OBJECTIVES: To evaluate the relationship between two common single nucleotide polymorphisms (SNPs) of CD40 gene (rs1883832 C/T and rs4810485 G/T) and the risk of immune thrombocytopenia (ITP) in the Egyptian population. METHODS: A case-control study was conducted retrospectively on 101 cases with ITP and 97 healthy subjects. Two SNPs of CD40 gene (rs1883832 C/T and rs4810485 G/T) were genotyped via Taqman allele discrimination real-time PCR. The frequencies of different genetic models of both SNPs were calculated and compared between ITP cases and controls. Linkage analysis was performed between the studied SNPs. Odds ratio (OR) and 95% confidence interval (CI) were assessed using multinomial logistic regression analysis to determine the association of CD40 gene SNPs genotypes, alleles, and haplotypes with the risk of ITP. The odds ratio was further adjusted to the confounders for risk stratification. RESULTS: CD40 (rs1883832) TT genotype carriers have a significantly higher risk of ITP when compared to CC genotype carriers (adjusted OR: 3.792, 95%CI: 1.252-11.49, P = 0.018). T allele also represents 1.711-fold increased risk of ITP which is more evident in males (P = 0.016). No significant difference was observed in the frequency of CD40 (rs4810485 G/T) genetic models between cases and controls. Linkage disequilibrium was found between the two SNPs and revealed four main haplotypes (C-G; C-T; T-G; T-T) with a significantly higher frequency of T-G haplotype in ITP cases than in healthy controls which confers an increased risk of ITP development (OR: 2.349, 95%CI: 1.271-4.339, P = 0.006). CONCLUSIONS: CD40 gene SNP rs1883832 is associated with an increased risk of ITP development in the Egyptian population, while the SNP rs4810485 has no association. Moreover, T-G haplotype is a risk genetic model for ITP.