Candidate gene association study in pediatric acute lymphoblastic leukemia evaluated by Bayesian network based Bayesian multilevel analysis of relevance

Background: We carried out a candidate gene association study in pediatric acute lymphoblastic leukemia (ALL) to identify possible genetic risk factors in a Hungarian population. Methods: The results were evaluated with traditional statistical methods and with our newly developed Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method. We collected genomic DNA and clinical data from 543 children, who underwent chemotherapy due to ALL, and 529 healthy controls. Altogether 66 single nucleotide polymorphisms (SNPs) in 19 candidate genes were genotyped. Results: With logistic regression, we identified 6 SNPs in the ARID5B and IKZF1 genes associated with increased risk to B-cell ALL, and two SNPs in the STAT3 gene, which decreased the risk to hyperdiploid ALL. Because the associated SNPs were in linkage in each gene, these associations corresponded to one signal per gene. The odds ratio (OR) associated with the tag SNPs were: OR = 1.69, P = 2.22x10-7 for rs4132601 (IKZF1), OR = 1.53, P = 1.95x10-5 for rs10821936 (ARID5B) and OR = 0.64, P = 2.32x10-4 for rs12949918 (STAT3). With the BN-BMLA we confirmed the findings of the frequentist-based method and received additional information about the nature of the relations between the SNPs and the disease. E.g. the rs10821936 in ARID5B and rs17405722 in STAT3 showed a weak interaction, and in case of T-cell lineage sample group, the gender showed a weak interaction with three SNPs in three genes. In the hyperdiploid patient group the BN-BMLA detected a strong interaction among SNPs in the NOTCH1, STAT1, STAT3 and BCL2 genes. Evaluating the survival rate of the patients with ALL, the BN-BMLA showed that besides risk groups and subtypes, genetic variations in the BAX and CEBPA genes might also influence the probability of survival of the patients. Conclusions: In the present study we confirmed the roles of genetic variations in ARID5B and IKZF1 in the susceptibility to B-cell ALL. With the newly developed BN-BMLA method several gene-gene, gene-phenotype and phenotype-phenotype connections were revealed. We showed several advantageous features of the new method, and suggested that in gene association studies the BN-BMLA might be a useful supplementary to the traditional frequentist-based statistical method

Non-alcoholic fatty liver infiltration in children: an underdiagnosed evolving disease

Non-alcoholic fatty liver disease (NAFLD) constitutes the most common liver disease, one that is still underdiagnosed in pediatric populations (as well as in the general population), this due to the progressive increase in childhood obesity observed both in developed and developing countries during the last few decades. The pathophysiology of the disease has not been thoroughly clarified yet. The condition displays common pathways in adults and children; however, there are age-related differences. Unlike adults, children with NAFLD require extensive laboratory analysis, because underlying pathologies other than obesity may contribute to the evolution of the disease. Despite the presence of several serum markers and imaging techniques that contribute to NAFLD diagnosis, liver biopsy remains the gold standard diagnostic procedure. Early intervention and obesity prevention are mandatory, as NAFLD is reversible at an early stage. If left undiagnosed and untreated, NAFLD can progress to steatohepatitis (NASH) and subsequent liver failure, a potentially lethal complication. Of note, there are no treatment options when advanced liver fibrosis occurs. This review summarizes literature data on NAFLD in childhood indicating that this is an evolving disease and a significant component of the metabolic syndrome. Pediatricians should be aware of this entity, screening children at high risk and providing appropriate early management, in collaboration with pediatric subspecialists. © 2019, Hellenic Endocrine Society

The role of BCL2 family of apoptosis regulator proteins in acute and chronic leukemias

The disturbance of apoptosis molecular signaling pathways is involved in carcinogenesis. BCL2 family of proteins is the hallmark of apoptosis regulation. In the last decade, new members of BCL2 gene family were discovered and cloned and were found to be differentially expressed in many types of cancer. BCL2 protein family, through its role in regulation of apoptotic pathways, is possibly related to cancer pathophysiology and resistance to conventional chemotherapy. It is well known that leukemias are haematopoietic malignancies characterized by biological diversity, varied cytogenetics, different immunophenotype profiles, and diverse outcome. Current research focuses on the prognostic impact and specific role of these proteins in the pathogenesis of leukemias. The understanding of the molecular pathways that participate in the biology of leukemias may lead to the design of new therapies which may improve patients' survival. In the present paper, we describe current knowledge on the role of BCL2 apoptosis regulator proteins in acute and chronic leukemias. Copyright © 2012 Flora Tzifi et al

Congenital cataracts, facial dysmorphism, and neuropathy syndrome

Congenital cataracts, facial dysmorphism, and neuropathy syndrome is a delineated genetic disease exclusively manifested in the Roma population. The pattern of inheritance is autosomal recessive, and a causative mutation is evident in the CTDP1 gene. Affected patients display congenital cataracts, microcornea, peripheral neuropathy, mild facial dysmorphism, hypogonadism, and psychomotor delay. We present the second case of this syndrome in a Greek Roma family, diagnosed in early infancy, along with the prenatal diagnosis in a subsequent pregnancy. © 2011 Elsevier Inc. All rights reserved

Flow cytometric analysis of the CD4+ TCR Vβ repertoire in the peripheral blood of children with type 1 diabetes mellitus, systemic lupus erythematosus and age-matched healthy controls

Background: Data regarding the quantitative expression of TCR Vβ subpopulations in children with autoimmune diseases provided interesting and sometimes conflicting results. The aim of the present study was to assess by comparative flow cytometric analysis the peripheral blood CD4+ TCR Vβ repertoire of children with an organ-specific autoimmune disorder, such as type 1 diabetes mellitus (T1DM), in comparison to children with a systemic autoimmune disease, such as Systemic Lupus Erythematosus (SLE) in comparison to healthy age-matched controls of the same ethnic origin. The CD4+ TCR Vβ repertoire was analysed by flow cytometry in three groups of participants: a) fifteen newly diagnosed children with T1DM (mean age: 9.2 ± 4.78 years old), b) nine newly diagnosed children with SLE, positive for ANA and anti-dsDNA, prior to treatment (mean age: 12.8 ±1.76 years old) and c) 31 healthy age-matched controls (mean age: 6.58 ± 3.65 years old), all of Hellenic origin.Results: CD4 + TCR Vβ abnormalities (± 3SD of controls) were observed mainly in SLE patients. Statistical analysis revealed that the CD4 + Vβ4 chain was significantly increased in patients with T1DM (p < 0.001), whereas CD4 + Vβ16 one was significantly increased in SLE patients (p < 0.001) compared to controls.Conclusions: CD4 + Vβ4 and CD4 + Vβ16 chains could be possibly involved in the cascade of events precipitating the pathogenesis of T1DM and SLE in children, respectively. © 2013 Tzifi et al.; licensee BioMed Central Ltd