The holistic approach to the CHRNA7 gene, hsa-miR-3158-5p, and 15q13.3 hotspot CNVs in migraineurs.

Migraine is a neurological disease characterized by severe headache attacks. Combinations of different genetic variations such as copy number variation (CNV) in a gene and microRNA (miRNA) expression can provide a holistic approach to the disease as a pathophysiological, diagnostic, and therapeutic target. CNVs, the Cholinergic Receptor Nicotinic Alpha 7 Subunit (CHRNA7) gene, and expression of gene-targeting miRNAs (hsa-miR-548e-5p and hsa-miR-3158-5p) in migraineurs (n = 102; with aura, n = 43; without aura, n = 59) and non-migraines (n = 120) aged 15-60 years, comparative, case-control study was conducted. Genetic markers were compared with biochemical parameters (BMI, WBC, Urea, GFR, ESR, CRP, HBG). All analyzes were performed by quantitative Real-Time PCR (q-PCR) and fold change was calculated with the 2-ΔΔCT method. The diagnostic power of the CHRNA7 gene, CNV, and miRNAs were analyzed with the receiver operating curve (ROC). CHRNA7 gene and hsa-miR-3158-5p are down-regulated in migraineurs and the gene is controlled by this miRNA via CNVs (p < .05). Both deletion and duplication were detected in patients with migraine for CVN numbers (p = .05). The number of CNV deletions was higher than duplications. When CHRNA7-CNV-hsa-miR-3158-5p was modeled together in the ROC analysis, the area under the curve (AUC) was 0.805, and the diagnostic power was "good". In migraineurs, the CHRNA7 gene can be controlled by hsa-miR-3158-5p via CNVs to modulate the mechanism of pain. These three genetic markers have diagnostic potential and may be used in antimigraine treatments.

Uteroglobin gene polymorphism (G38A) may be a risk factor in childhood idiopathic nephrotic syndrome.

BACKGROUND: Uteroglobin (UG) is a multifunctional protein with anti-inflammatory properties. The aim of this study was to first evaluate the role of UG gene G38A polymorphism in childhood idiopathic nephrotic syndrome (INS), and determine whether this variation may be related to the occurrence of INS or a steroid response. METHODS: One hundred and thirty-six children diagnosed with INS in Gaziantep University, Department of Pediatric Nephrology, and 70 healthy volunteers were included. Children with INS were divided into two groups: steroid-sensitive (n = 84), and steroid-resistant (n = 52). Samples were examined using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) enzyme method. RESULTS: The distributions of AA, GG, and AG genotypes of UG gene G38A (G/A) were 16.9%, 44.9%, and 38.2% in the all-INS group, whereas they were 14.3%, 48.8%, and 36.9% in the steroid-sensitive INS (SSINS) group compared with 21.1%, 38.5%, and 40.4% in steroid-resistant INS (SRINS), and 5.7%, 41.4%, and 52.9% in controls. The risk of INS was increased almost 4-fold in children with the AA genotype (p = 0.016). The risk of having SSINS was increased 3.5-fold (p = 0.042) whereas the risk of SRINS was increased 4.8-fold in the same genotype (p = 0.014). CONCLUSIONS: The uteroglobin gene may play an important role in the development of INS, and the AA genotype of UG gene G38A polymorphism was found more frequently in those children. Further studies evaluating all polymorphisms in larger patient groups are needed to exactly determine the effect of UG gene on the development of INS and steroid response in children.

Association of TAP1 and TAP2 gene polymorphisms with hematological malignancies.

Transporter associated with antigen presenting (TAP) 1 and TAP2 genes are localized in the major histocompatability complex (MHC) class II region and form a heterodimer playing a key role in endogenous pathways for antigen presentation. Defects of these genes have been reported to be common in different types of cancer. Polymorphisms identified in these loci have also been investigated and reported to be associated with several autoimmune disorders, viral infections and neoplasms. In the present study, for the first time, the allele and genotype frequencies of TAP1-333, TAP2-565, TAP2-651 and TAP2-665 were determined in patients with hematological malignancies (HM) using a PCR-RFLP method and compared with the frequencies in the control group. Our results suggested an association of TAP1-333 polymorphism with multiple myeloma-MM and TAP2- 565 polymorphism with chronic lymphoid leukemia-CLL. In addition, it could be concluded that the TAP2-665 GG genotype might be a risk factor for all types of hematological malignancies included in this study.

Mitochondrial uncoupling protein 2 (UCP2) gene polymorphisms are associated with childhood obesity and related metabolic disorders.

OBJECTIVE: This study aimed to investigate the possible role of uncoupling protein 2 (UCP2) gene polymorphisms in childhood obesity and related metabolic disorders. METHODS: Obese patients (n=100) and healthy controls (n=100) were analyzed for -866G>A and insertion/deletion (I/D) polymorphisms of the UCP2 gene by polymerase chain raction and/or restriction fragment length polymorphism. RESULTS: UCP2 I/D polymorphism showed an association with obesity. The insertion homozygous genotype (II) was higher in obese patients (p=0.0001), while the DD genotype was higher in controls (p=0.0034). Body mass index and relative weight were lower in patients carrying the A allele of the -866G>A polymorphism (p=0.021 and p=0.047, respectively). There was an association between insulin resistance and -866A allele carrier patients with consanguineous parents (p=0.005). CONCLUSION: Insertion homozygous genotype and the allele of I/D polymorphism were found to be risk factors for childhood obesity and related metabolic disorders. The -866A allele was associated with susceptibility to central adiposity, hypercholesterolemia, hypertriglyceridemia and insulin resistance.

Association of an LMP2 polymorphism with acute myeloid leukemia and multiple myeloma.

Hematological malignancies (HM) are a group of neoplasms derived from the cells of the bone marrow and lymphatic system. Genetic factors leading to susceptibility to HM have been investigated for years but little is known yet. Low molecular weight polypeptide (LMP) 2 and LMP7 genes are important subunits of the immunoproteasome and play significant role in antigen presentation. The polymorphisms of LMP genes have been reported to be risk factors for various types of diseases. The aim of this study was to investigate the association of LMP2 and LMP7 polymorphisms with the occurrence of particular types of HM. A total of 132 patients with HM and 130 control subjects were investigated. No significant difference was obtained in the distribution of genotype and allele frequencies of LMP7 gene in HM patients and the control group. On the other hand, the prevalence of LMP2-AA genotype was found to be higher in acute myeolid leukemia (AML) patients while it was significantly lower in multiple myeloma (MM) cases than in the control subjects. Our results suggested that LMP7 could not be a risk factor for susceptibility to HM, whereas LMP2 polymorphisms could play a role in the development of AML and MM.

Association of macrophage migration inhibitory factor and mannose-binding lectin-2 gene polymorphisms in acute rheumatic fever.

BACKGROUND: Macrophage migration inhibitory factor and mannose-binding lectin-2 play important roles in the pathogenesis of several acute and chronic inflammatory/autoimmune disorders. The aim of the study was to investigate any possible association between migration inhibitory factor and mannose-binding lectin-2 gene polymorphisms and acute rheumatic fever in children. Material and methods A total of 38 unrelated children with acute rheumatic fever and 40 age- and sex-matched healthy controls were analysed for codon 54 A/B polymorphism in mannose-binding lectin-2 gene and -173 G/C polymorphism in migration inhibitory factor gene by using the polymerase chain reaction method. RESULTS: Frequency of BB genotype of mannose-binding lectin-2 gene was higher in the patient group. Interestingly, children with acute rheumatic fever with AA genotype tended to have chorea compared with children with BB genotype. There was a statistically significant increase in frequency of the migration inhibitory factor -173 CC genotype in patients compared with the control subjects. CONCLUSION: The present study is the first to investigate the mannose-binding lectin-2 gene polymorphism in children with acute rheumatic fever. BB genotype of mannose-binding lectin-2 (codon 54) and CC genotype of migration inhibitory factor (-173) may have a role in the immunoinflammatory process of acute rheumatic fever.

The polymorphisms of the MBL2 and MIF genes associated with Pediatric Cochlear Implant Patients.

OBJECTIVES: Mannose-binding lectin and macrophage migration inhibitory factor gene polymorphisms are associated with several acute/chronic autoimmune or inflammatory diseases. The aim of this study was to investigate if there was any association between mannose-binding lectin 2 (MBL2) and macrophage migration inhibitory factor (MIF) gene polymorphisms and profound congenital sensorineural hearing loss in children who underwent cochlear implantation. METHODS: A total of 62 patients with congenital hearing loss and 80 age- and sex-matched healthy controls were evaluated for codon 54 A/B polymorphisms in MBL2 and the-173 G/C polymorphism in MIF by using the polymerase chain reaction and restriction fragment length polymorphism method. RESULTS: The frequency of the BB genotype of MBL2 and MIF -173 GC genotype were statistically significantly higher in the patient group than in the controls (p=0.0127, p=0.0408, respectively). CONCLUSION: In this study, we found that a subject who is homozygous for the variant allele B of codon 54 of the MBL2and heterozygous for variant allele C of -173 MIF has a risk factor for sensorineural hearing loss.

Childhood obesity and the role of dopamine D2 receptor and cannabinoid receptor-1 gene polymorphisms.

AIMS: The dopaminergic and endocannabinoid systems are involved in regulation of feeding behavior. The aim of the study is to examine the possible relation between polymorphisms of the dopamine D2 receptor (DRD2) and cannabinoid receptor-1 (CNR1) genes and childhood obesity. METHODS: A hundred obese children and 100 healthy controls were analyzed for DRD2 Taq1A and Taq1B and CNR1 1359G/A polymorphisms. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: There were no statistically significant differences in DRD2 Taq1A and DRD2 Taq1B genotypes or allelic frequencies between obese children and controls (p>0.05). In patients with Taq1B2 allele, morbid obesity was less frequent (p=0.010). The frequency of the A allele of CNR1 1359G/A polymorphism was significantly higher in obese children than in controls (21.0% vs. 13.0%, p=0.0166). The frequency of genotypes AG and GG of the CNR1 1359G/A SNP was different between obese children and control subjects (for AG: 34.0% vs. 22.0%, p=0.0294; for GG: 62.0% vs. 76.0%, p=0.0162, respectively). CONCLUSIONS: No significant difference was found between genotypes and alleles of DRD2 Taq1A and DRD2 Taq1B polymorphism in patients and controls, while the CNR1 receptor 1359G/A polymorphism and the presence of the A allele may be one risk factor for susceptibility to obesity.

Mannose binding lectin and macrophage migration inhibitory factor gene polymorphisms in Turkish children with cardiomyopathy: no association with MBL2 codon 54 A/B genotype, but an association between MIF -173 CC genotype.

Myocardial inflammation is one of the commonest mechanisms in cardiomyopathy (CMP). Mannose binding lectin (MBL) is a key molecule in innate immunity, while macrophage migration inhibitory factor (MIF) is a constitutive element of the host defenses. We investigated the possible association between polymorphisms of MBL2 and MIF genes and CMP in Turkish children. Twenty-children with CMP and 30 healthy controls were analyzed for codon 54 A/B polymorphism in MBL, and -173 G/C polymorphism in MIF genes by using PCR-RFLP methods. No significant difference was found between genotypes and alleles of MBL2 gene codon 54 A/B polymorphism in patients and controls (p>0.05). However, serum uric acid levels was found higher in dilated CMP patients with AA genotype. Frequency of MIF -173 CC genotype was significantly higher in patients (p<0.05), and sodium levels were higher in patients with MIF -173 CC genotype. This study is the first to investigate the MBL and MIF gene polymorphisms in Turkish children with CMP. We conclude that CC genotype of MIF (-173) polymorphism may be a risk factor for CMP patients. However, further studies with larger samples are needed to address the exact role of this polymorphism in CMP.

Role of cytokine gene (IFN-γ, TNF-α, TGF-ß1, IL-6, and IL-10) polymorphisms in pathogenesis of acute rheumatic fever in Turkish children.

UNLABELLED: Acute rheumatic fever (ARF) is a delayed immunologically mediated sequela of throat infection by group A ß-hemolytic streptococci. Inflammatory cytokines may play a pathogenic role in ARF. The objective of this study was to investigate the potential associations between interferon (IFN)-γ, interleukin (IL)-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1, and IL-10 gene polymorphisms and childhood ARF. Thirty-eight ARF patients and 40 age- and sex-matched healthy controls were analyzed for eight polymorphisms in five different cytokine genes [IFN-γ (+874), IL-6 (-174), TNF-α (-308), TGF-ß1 (+10, +25), and IL-10 (-1082, -819, -592)]. Cytokine genotyping was performed by polymerase chain reaction sequence-specific primer methods. Patients with ARF had significantly higher frequencies of IFN-γ (+874) polymorphism in both TT genotype (p=0.0002) and T allele (p=0.0004). No statistically significant differences were observed in genotypes, haplotypes, and allele frequencies of IL-6, TNF-α, TGF-ß1, and IL-10 genes between ARF and control groups (p>0.05). GG genotype frequency of TNF-α gene (low expression) was higher in patients who had previous ARF history (p=0.006). High expression of TGF-ß1 (TT/GG, TC/GG) was more frequent in patients with CRP positivity (p=0.034). IL-6 CC genotype (low expression) frequency was higher in patients with tricuspid valve insufficiency (p=0.002), while IFN-γ TT genotype (high expression) frequency was higher in patients with mitral valve prolapse (p=0.049). CONCLUSION: High expression of the IFN-γ gene may carry a higher risk for ARF in Turkish children, while IL-6, TNF-α, and TGF-ß1 may have an impact in mediating some clinical and laboratory manifestations of the disease.

Learning disability and oligodendrocyte myelin glycoprotein (OMGP) gene in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease where phenotypic heterogeneity is explained by the effect of modifier genes. Thirty to 65% of patients have learning disability. The oligodendrocyte myelin glycoprotein (OMGP) gene located within the neurofibromatosis type 1 (NF1) gene might affect the phenotype of learning disability because it is expressed in the brain, and OMGP gene mutations have been associated with cognitive disturbances. We analyzed the OMGP gene in NF1 patients with and without learning disability (n = 50 each) and healthy controls (n = 100). The allele distribution of OMGP62 polymorphism was not significantly different between the groups (p = 0.447). These results do not support a relationship between the OMGP gene and the learning disability phenotype observed in NF1. Other modifying genes, post-translational modifications or receptor interactions might be involved in the phenotypic variability of NF1.