Hasibe Verdi

Genetic Mutations in Turkish Population With Pulmonary Embolism and Deep Venous Thrombosis

Venous thromboembolism (VTE) is a universal health hazard. Inherited and acquired risk factors increase the risk of VTE. We evaluated the relationship between factor V (G1691A, A1090G, and A1299G), prothrombin (PT G20210A), methylenetetrahydrofolate reductase (MTHFR C677T) mutations, plasminogen activator inhibitor 1 (PAI-1 -675) polymorphism, and VTE in Turkish population. In all, 80 patients with VTE and 104 controls were included. Heterozygous factor V Leiden (FVL) mutation was significantly higher among patients (P = .04) with allele frequency of 6.3% (P = .01). Heterozygous PT G20210A mutation was also significantly higher among patients (P = .001) with allele frequency of 6.9% (P = .003). MTHFR 677TT genotype was significantly higher in patients (P = .009) with allele frequency of 23.8% (P = .005). No significant difference was found in FV A1090G and FV A1299G mutation rate as well as PAI-1 genotypes and their allele frequencies (P > .05). Thus, frequencies of FV G1691A, PT G20210A, and MTHFR C677T mutations are higher in patients with VTE. FV A1090G, FV A1299G mutations, and PAI-1 gene polymorphisms may not be a risk factor for VTE in Turkish population.

Maternal–Fetal Proinflammatory Cytokine Gene Polymorphism and Preterm Birth

Association between maternal-fetal proinflammatory cytokine genotype and preterm birth was studied. Isolated genomic DNA from maternal and cord blood samples of 100 preterm and 101 term labors were used for TNFα (-238G/A, -308G/A), IL-1α (4845G/T), and IL-1β (-511C/T) genotyping. TNFα -238 GA genotype in term neonates was significantly higher than the premature neonates (p<0.05). Maternal-fetal TNFα -238 heterozygosity was associated with term labor (p<0.05). TNFα -308 GA and AA genotypes were associated with term labor (mothers and neonates, respectively; p<0.05 and p<0.001). The incidence of term labor was significantly increased in TNFα -308 GA genotype. If a -308GA carrier has a fetus with GG genotype, the incidence of preterm labor increases (p<0.01). The 4845 T allele was significantly higher in preterm mothers and neonates (p<0.001 and p<0.001). The effect of maternal-fetal genotype for the pregnancy outcome reveals that maternal 4845GG and GT genotypes increase term labor incidence, whereas fetal 4845 TT genotype was a significant independent risk factor for preterm birth (p<0.01). IL-1β -511 TT genotype was significantly higher in preterm neonates. The preterm labor risk was significantly increased in maternal -511 TT genotype and fetal CT genotypes, whereas with maternal -511 CT or TT genotypes or a -511 TT fetus, the incidence of term pregnancy increases (p<0.01).

PAI-1 gene 4G/5G polymorphism, cytokine levels and their relations with metabolic parameters in obese children

Obesity is associated with the changes of plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-alpha (TNFalpha) and transforming growth factor beta (TGFbeta) levels. However, the precise effect of the 4G allele on obesity is still contradictory. Here, we aimed to elucidate the role of the 4G/5G polymorphism of the PAI-1 gene on the PAI-1 level and determine the associations between cytokines, glucose and lipid metabolism parameters in obese children. Thirty-nine obese children (mean age 11.4 +/- 3.3 years) and 38 age-matched healthy control group (mean age 10.3 +/- 3.5 years) were included in the study. In all cases, serum levels of glucose, lipid and insulin were measured, homeostasis model assessment of insulin resistance (HOMA-IR) was calculated, and 4G/5G polymorphism of PAI-1 gene, plasma PAI-1 level and serum TNFalpha and TGFbeta levels were studied. The mean relative body mass index (BMI) and HOMA-IR score, VLDL, TG, insulin, PAI-1, TNFalpha levels were higher, and HDL and TGFbeta levels were lower in the obese group. The frequency of the 4G/4G genotype was considerably higher in obese children than in controls. Also, a positive correlation was found between PAI-1 and TNFalpha levels, and relative BMI, HOMA-IR score, insulin, TG, HDL levels. TGFbeta was inversely correlated only with relative BMI. There was no correlation among three cytokines. In conclusion, childhood obesity contributes to higher PAI-1 and TNFalpha and lower TGFbeta levels. Especially PAI-1 and TNFalpha accompany insulin resistance and dyslipidemia.

Prevalence of Thrombophilic Mutations and ACE I/D Polymorphism in Turkish Ischemic Stroke Patients

The aim of this study was to evaluate the prevalence of factor V Leiden (FVL), prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T gene mutations, and angiotensin-converting enzyme (ACE) I/D polymorphism in ischemic stroke (IS) patients. A total of 162 Turkish IS patients were included and analyzed according to stroke subtype by the TOAST classification. Their genotype data were compared with those of the control group, representing the healthy population, using the χ2 test. The frequency of FVL heterozygocity was 12.3% in this series—higher than that in the normal population (9.8%; statistically insignificant, P = .478). The frequency of the ACE D/D genotype in all stroke patients and those with stroke of undetermined etiology was higher than that in our population (52.5% and 59.2%, respectively, vs 39.3%; statistically significant, P = .034, P = .020). Our results may suggest that ACE D/D genotype is a risk factor for IS, particularly in those with stroke of undetermined etiology in the Turkish population.

Analysis of prothrombotic mutations and polymorphisms in children who developed thrombosis in the perioperative period of congenital cardiac surgery.

In this study, we investigated some of the prothrombothic mutations and polymorphisms in 15 children with congenital cardiac malformations who developed severe thrombosis in the perioperative period following surgical repair. The mutations and polymorphisms included in the study were Factor V Leiden, prothrombin G20210A, methylentetrahydrofolate reductase C677T, endothelial nitric oxide synthase intron 4 VNTR, alpha-fibrinogen Thr312Ala, Factor XIII Val34Leu, and insertion or deletion of angiotensin 1 converting enzyme. Compared to the healthy Turkish subjects, our patients had a similar rate of mutation of Factor V Leiden, Factor XIII Val34Leu, and endothelial nitric oxide synthase a/b polymorphisms, but higher frequency of the prothrombotic angiotensin 1 converting enzyme deletion/deletion genotype, and lower frequency of the antithrombotic alpha fibrinogen Thr/Thr genotype. None of the patients exhibited mutations involving prothrombin G20210A or methylentetrahydrofolate reductase C677T. The results of our study suggest that, in addition to prothrombotic mutations such as Factor V Leiden, single-nucleotide polymorphisms should be considered in all children with congenital cardiac malformations who develop thrombosis. Malformations of the heart are the most common of all serious lesions that are present at birth, with an incidence of 4 to 8 cases per 1,000 live births. If needed, corrective surgery is usually the optimal treatment for these anomalies, but perioperative morbidity and mortality still remain high due to several factors. Arterial or venous thrombosis, or both varieties of thrombosis, is among these factors. Prior to surgery, the most frequent time at which these children develop thrombosis is during cardiac catheterization. Postoperative thrombosis in this group of patients is a more complex disorder, which can affect both small and large vessels, and is associated with a high morbidity and mortality. Recent studies indicate that both point mutations and single-nucleotide polymorphisms of genes that encode proteins involved in the coagulative and anticoagulative cascades are important risk factors for development of thrombosis. Patients with these risk factors are most likely to develop thrombosis when triggering elements, such as placement of catheters, prolonged immobilization, or surgery, are also present. In this study, we investigated some of the above-mentioned mutations and polymorphisms in children who developed thrombosis in the perioperative period after correction of congenital cardiac malformations.

Methylenetetrahydrofolate Reductase C677T Mutation and Nonalcoholic Fatty Liver Disease

A mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is known as one of the causes of hyperhomocyteinemia. The oxidation products of homocysteine can initiate lipid peroxidation, which has a central role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We aimed to assess the possible role of the MTHFR C677T mutation in the progression of simple steatosis to an advanced form of NAFLD. Thirty-four patients with NAFLD diagnosed by histologic analysis and 282 healthy controls were included in the study. The discrimination of nonalcoholic steatohepatitis (NASH) from another NAFLD was made by NAFLD activity score (NAS), and a NAS≥5 was considered NASH. Patients with either NASH or nonalcoholic fatty liver (NAFL) and controls were evaluated for frequency of the MTHFR C677T mutation. The frequency of the MTHFR C677T mutation was 53.5% (CT, 44.7%; TT, 8.9%) in controls and 41.5% (CT, 37.7%; TT, 3.8%) in patients (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.34–1.12). There was no statistical difference in the frequency of this genotype between patients with NAFL and those with NASH (36% [CT, 28%; TT, 8%] vs 46.4% [CT, 46.4; TT, 0%]; OR, 0.65; 95% CI, 0.22–1.96). According to this study, the MTHFR C677T mutation does not seem to be a risk factor for the progression of NAFL to NASH.

Purpura fulminans in a child with combined heterozygous prothrombin G20210A and factor V Leiden mutations

Although thrombosis is relatively rare in children, reports of young patients with thrombosis are becoming more frequent with time. Activated protein C resistance and prothrombin 20210 A mutation are results of point mutations described in the last decade. This article highlights a case of a child with severe arterial thrombosis who was heterozygous for the factor V Leiden (FVL) and prothrombin G20210A mutations. The patient diagnosed with purpura fulminans was an 8-year-old boy who was referred to our hospital with purpuric lesions on the extremities and necrosis of the penis. We believe that the coexistence of more than one thrombophilic mutation contributed to the occurrence of severe thrombosis at a young age in this patient.

Involvement of Toll-like receptors in cervical cancer susceptibility among Tunisian women

Previous studies underscored the importance of genetic factors in the pathogenesis of certain cancers, including cervical cancer. Epidemiological evidence supports an association between specific polymorphisms of Toll-like receptors (TLR) with several human pathological states, including cervical cancer. The aim of this study was to investigate the link between specific gene variants in TLR2 (-196 to -174 del), TLR3 (c.1377 C>T), TLR4 (Asp299Gly), and TLR9 (2848 G>A) and susceptibility to cervical cancer in Tunisian women. Study subjects comprised 122 women with histopathologically-confirmed cervical cancer, and 260 unrelated age- and ethnically-matched healthy females, who served as controls. TLR genotyping was done using PCR-restriction fragment length polymorphism. The C/C genotype of TLR3 (c.1377 C>T) is associated with cervical cancer susceptibility (OR: 1.71, CI: 1.08-2.70). For TLR4 (Asp299Gly), the Asp/Asp genotype and the Asp allele were associated with higher risk of developing cervical cancer (OR: 4.95, CI: 1.97-13.22) and (OR: 5.17, CI: 2.11-13.50) respectively. We demonstrated no association between the TLR2 (-196 to -174 del) and the TLR 9 (2848 G>A) polymorphisms and the susceptibility of cervical cancer among Tunisian women. However, the C/C genotype for the TLR3 (c.1377 C>T) polymorphism and the Asp/Asp genotype and the Asp allele for (Asp299Gly) TLR4 polymorphism were found to be associated with a higher risk of cervical cancer.

The effect of plasminogen activator inhibitor-1 gene 4G/5G polymorphism on glucose and lipid metabolisms in Turkish obese children

Objective Obesity is a metabolic disorder that is associated with increased plasminogen activator inhibitor‐1 (PAI‐1) concentration in the circulation. This increase is related to insulin resistance, dyslipidaemia and cardiovascular disease. Some studies have demonstrated a relationship between plasma PAI‐1 concentrations and the 4G/5G gene polymorphism in the PAI‐1 gene, while other studies have not. It is well known that plasma PAI‐1 levels are increased in obesity; however, the relationship between the polymorphism and obesity remains unclear. In this study, we aimed to elucidate the effect of the PAI‐1 4G/5G polymorphism on glucose and lipid metabolism parameters in Turkish obese children.

Atypical phenotypes of DYT1 dystonia in three children.

UNLABELLED DYT-1 dystonia is the most common primary dystonia seen in childhood. It is an autosomal dominantly inherited disorder caused by deletion of a GAG triplet in exon 5 of the DYT1 gene. It characteristically starts in a distal limb during late childhood, subsequently spreads to involve other body regions sparing oromandibular muscles. However, clinical presentation can vary remarkably with respect to age, site of onset and progression. In this study we present three early-onset DYT-1 dystonia patients who are atypical according to age of onset and localization. Dystonia has started at 2, 3 and 7years of age and generalized to involve other limbs in all patients and also oromandibular muscles in one patient. None of them have benefited from medical treatments including L-dopa. All had normal brain MRI scan, a history of normal birth without significant perinatal asphyxia, infection or trauma and all are neurodevelopmentally otherwise normal. CONCLUSION In children with dystonia; if brain imaging is unremarkable and when there is no history of CNS disorders such as perinatal asphyxia, infections, drug exposure or trauma; genetic analysis for GAG deletion of DYT-1 gene may be performed even if dystonia starts at a very young age or it spreads to involve oromandibular muscles.