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Öğe A study of cancer-related genes: Prevalence of polymorphic GSTT1 and GSTM1 deletions in Turkey(2013) Karaca, Şefayet; Karaca, Mehmet; Kaymaz, AyşeThe major burden of cancer in the general population is results from the complex interactions of multiple genetic and environmental factors over time. Population based studies support the involvement of GSTM1 and GSTT1 deletion in susceptibility to commonly occurring forms of cancer. The aim of this study was to determine frequency of GSTM1 and GSTT1 deletion variants in Turkish population. Deletion polymorphisms were screened in a collection of samples n=507 for GSTM1 and n=464 for GSTT1. After isolation of DNAs from whole blood, sequences of interest were amplified and then analyzed by electrophoretic methods in the presence of positive and negative controls. Allele frequencies were detected as 52% for GSTM1 and 24% for GSTT1 deletion polymorphisms. The obtained frequencies were consistent with the values that reported for different populations. Cancer is a disease of the genome and identification of the genetic characteristics of healthy individuals is important in determining of current risks, developing of preventive health care models and medical follow-up programs to reducing risk of diseases. However, during the treatment process it allows the selection of optimal therapy.Öğe Allergy-specific phenome-wide association study for ımmunogenes in Turkish children(Nature Publishing Group, 2016) Karaca, Şefayet; Civelek, Ersoy; Karaca, Mehmet; Şahiner, Ümit M.; Özgul, Rıza K.; Kocabaş, Can N.; Polimanti, Renato; Sekerel, Bülent E.To dissect the role of immunogenetics in allergy and asthma, we performed a phenome-wide association study in 974 Turkish children selected from a cross-sectional study conducted using ISAAC (International Study of Asthma and Allergies in Children) Phase II tools. We investigated 9 loci involved in different immune functions (ADAM33, ADRB2, CD14, IL13, IL4, IL4R, MS4A2, SERPINE1, and TNF) with respect to 116 traits assessed through blood tests, hypertonic saline challenge tests, questionnaires, and skin prick tests. Multiple associations were observed for ADAM33: rs2280090 was associated with reduced MEF240% (i.e., the ratio of Mean Expiratory Flow after 240s of hypertonic saline inhalation with respect to the age-and ancestry-matched reference value) and with an increased risk of allergic bronchitis (p = 1.77*10(-4) and p = 7.94*10(-4), respectively); rs3918396 was associated with wheezing and eczema comorbidity (p = 3.41*10(-4)). IL4 rs2243250 was associated with increased FEV240 (Forced Expiratory Flow Volume after 240s of hypertonic saline inhalation; p = 4.81*10(-4)) and CD14 rs2569190 was associated with asthma diagnosis (p = 1.36*10(-3)). ADAM33 and IL4 appeared to play a role in the processes linked to allergic airway inflammation and lung function. Due to its association with wheezing and eczema comorbidity, ADAM33 may also be involved in the atopic march.Öğe Asthma-specific phenome-wide association study for immunogenes in Turkish asthmatic children(Wiley-Blackwell, 2016) Civelek, Ersoy; Polimanti, R.; Karaca, Seda; Karaca, Mehmet; Şahiner, Ümit Murat; Kocabaş, Can Naci; Kalayci, C. O.; Sekerel, B. E.[Abstract Not Available]Öğe Clinical relevance of VKORC1 genotype and response to warfarin therapy(Wiley-Blackwell, 2014) Karaca, Sefayet; Karaca, Mehmet; Coşgun, Erdal; Aksoy, Neşe Hayat; Bozkurt, Nujen Çolak[Abstract Not Available]Öğe Detection of biotinidase gene mutations in Turkish patients ascertained by newborn and family screening(Sprınger, 2015) Karaca, Mehmet; Özgül, Rıza Köksal; Ünal, Özlem; Yücel Yılmaz, Didem; Kılıç, Mustafa; Hişmi, Burcu; Tokatlı, Ayşegül; Coşkun, TurgayThe incidence of biotinidase deficiency in Turkey is currently one of the highest in the world. To expand upon the information about the biotinidase gene (BTD) variations in Turkish patients, we conducted a mutation screening in a large series (n = 210) of probands with biotinidase deficiency, using denaturing high-performance liquid chromatography and direct DNA sequencing. The putative effects of novel mutations were predicted by computational program. Twenty-six mutations, including six novels (p.C143F, p.T244I, c.1212-1222del11, c.1320delG, p.V457L, p.G480R) were identified. Nine of the patients were symptomatic at the initial clinical assessment with presentations of seizures, encephalopathy, and lactic acidemia. The most common mutation in this group of symptomatic patients was c.98-104 del7ins3. Among the screened patients, 72 have partial and 134 have profound biotinidase deficiency (BD) of which 106 are homozygous for BTD mutations. The common mutations (p.R157H, p.D444H, c.98-104del7ins3, p.T532M) cumulatively accounted for 72.3 % of all the mutant alleles in the Turkish population. Conclusion: The identification of common mutations and hot spot regions of the BTD gene in Turkish patients is important for mutation screening in the Turkish population and helps to ascertain carriers, may have impact on genetic counseling and implementing prevention programs.Öğe Evaluation and identification of ıdua gene mutations in turkishpatients with mucopolysaccharidosis type I(2016) Atçeken, Nazente; Özgül, Rıza Köksal; Yücel Yılmaz, Didem; Tokatlı, Ayşegül; Coşkun, Turgay; Sivri, Hatice Serap; Dursun, Ali; Karaca, MehmetBackground/aim: This study aimed to identify IDUA gene mutations in Turkish patients morphologically (phenotypic) diagnosed with MPS type I. It also sought to discuss the possible effects of detected mutations on alpha-L-iduronidase enzyme function based on current knowledge. Materials and methods: Genetic analysis was carried out in 15 patients using direct DNA sequencing. Moreover, segregation analysis was performed among family members to predict the pathogenic effect of novel mutations, and computational programs were used to predict their functional impact. Results: Nine different mutations (c.494-1G>A, c.793-6C>G, c.793-5C>A, p.M1L, p.Y64X, p.A327P, p.W402X, p.P533L, and p.R628X) were identified. Computational analysis results supported the pathogenicity of novel mutations, suggesting improper splicing. Seven already-known polymorphisms were detected in the screened cohort as well. Conclusion: Our results revealed heterogeneity in the mutation spectrum of Turkish patients. Six of the mutations, including the novel ones, have never before been reported in the Turkish population. Moreover, 5 patients who were phenotypically diagnosed with MPS type I could not be confirmed by genetic analysis, indicating the importance of the molecular characterization of MPS subtypes.Öğe Genetic diversity of disease-associated loci in Turkish population(Nature Publishing Group, 2015) Karaca, Şefayet; Cesuroğlu, Tomris; Karaca, Mehmet; Erge, Sema; Polimanti, RenatoMany consortia and international projects have investigated the human genetic variation of a large number of ethno-geographic groups. However, populations with peculiar genetic features, such as the Turkish population, are still absent in publically available datasets. To explore the genetic predisposition to health-related traits of the Turkish population, we analyzed 34 genes associated with different health-related traits (for example, lipid metabolism, cardio-vascular diseases, hormone metabolism, cellular detoxification, aging and energy metabolism). We observed relevant differences between the Turkish population and populations with non-European ancestries (that is, Africa and East Asia) in some of the investigated genes (that is, AGT, APOE, CYP1B1, GNB3, IL10, IL6, LIPC and PON1). As most complex traits are highly polygenic, we developed polygenic scores associated with different health-related traits to explore the genetic diversity of the Turkish population with respect to other human groups. This approach showed significant differences between the Turkish population and populations with non-European ancestries, as well as between Turkish and Northern European individuals. This last finding is in agreement with the genetic structure of European and Middle East populations, and may also agree with epidemiological evidences about the health disparities of Turkish communities in Northern European countries.Öğe Genotypic-phenotypic features and enzyme replacement therapy outcome in patients with mucopolysaccharidosis VI from Turkey(Wiley, 2017) Kılıç, Mustafa; Dursun, Ali; Coşkun, Turgay; Tokatlı, Ayşegül; Özgül, Rıza K.; Yücel Yılmaz, Didem; Karaca, Mehmet; Doğru, Deniz; Alehan, Dursun; Kadayıfcılar, Sibel; Genç, Aydan; Turan Dizdar, Handan; Gönüldas, Burhanettin; Savcı, Sema; Sağlam, Melda; Aksoy, Cemalettin; Arslan, Umut; Sivri, Hatice SerapMucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disorder (LSD) characterized by a chronic, progressive course with multiorgan involvement. In our study, clinical, biochemical, molecular findings, and response to enzyme replacement therapy (ERT) for at least 6 months were evaluated in 20 patients with MPS VI. Treatment effects on clinical findings such as liver and spleen sizes, cardiac and respiratory parameters, visual and auditory changes, joints' range of motions, endurance tests and changes in urinary glycosaminoglycan excretions, before and after ERT were analyzed. ERT caused increased physical endurance and decreased urinary dermatan sulfate/chondroitin sulfate ratios. Changes in growth parameters, cardiac, respiratory, visual, auditory findings, and joint mobility were not significant. All patients and parents reported out an increased quality of life, which were not correlated with clinical results. The most prevalent mutation was p.L321P, accounting for 58.8% of the mutant alleles and two novel mutations (p.G79E and p.E390K) were found. ERT was a safe but expensive treatment for MPS VI, with mild benefits in severely affected patients. Early treatment with ERT is mandatory before many organs and systems are involved.Öğe GSTM1, GSTP1, and GSTT1 genetic variability in Turkish and worldwide populations(Wiley-Blackwell, 2015) Karaca, Şefayet; Karaca, Mehmet; Cesuroğlu, Tomris; Erge, Sema; Polimanti, RenatoObjective: Glutathione S-transferase (GST) variants have been widely investigated to better understand their role in several pathologic conditions. To our knowledge, no data about these genetic polymorphisms within the Turkish population are currently available. The aim of this study was to analyze GSTM1 positive/null, GSTT1 positive/null, GSTP1*I105V (rs1695), and GSTP1*A114V (rs1138272) variants in the general Turkish population, to provide information about its genetic diversity, and predisposition to GST-related diseases. Methods: Genotyping was performed in 500 Turkish individuals using the Sequenom MassARRAY platform. A comparative analysis was executed using the data from the HapMap and Human Genome Diversity Projects (HGDP). Sequence variation was deeply explored using the Phase 1 data of the 1,000 Genomes Project. ResultsThe variability of GSTM1, GSTT1, and GSTP1 polymorphisms in the Turkish population was similar to that observed in Central Asian, European, and Middle Eastern populations. The high linkage disequilibrium between GSTP1*I105V and GSTP1*A114V in these populations may have a confounding effect on GSTP1 genetic association studies. In analyzing GSTM1, GSTT1, and GSTP1 sequence variation, we observed other common functional variants that may be candidates for associated studies of diseases related to GST genes (e.g., cancer, cardiovascular disease, and allergy). Conclusions: This study provides novel data about GSTM1 positive/null, GSTT1 positive/null, GSTP1*I105V, and GSTP1*A114V variants in the Turkish population, and other functional variants that may affect GSTM1, GSTT1, and GSTP1 functions among worldwide populations. This information can assist in the design of future genetic association studies investigating oxidative stress-related diseases. Am. J. Hum. Biol. 27:310-316, 2015. (c) 2014 Wiley Periodicals, Inc.Öğe Haplotype analysis of non-HLA immunogenetic loci in Turkish and worldwide populations(Elsevier Science Bv, 2016) Karaca, Şefayet; Karaca, Mehmet; Civelek, Ersoy; Özgül, Rıza Köksal; Şekerel, Bülent Enis; Polimanti, RenatoImmunogenes (i.e., genes related to the immune system and its functions) are involved in the predisposition to numerous traits and their variation contributes to the phenotypic variability observed among human groups. Turkish population presents particular genetic features since its genetic pool is an admixture of European, Middle-Eastern, and Central Asian ancestries. Here, we analyzed the haplotype structure of four immunogenetic loci (i.e., ADAM33; IL13-IL4; IL4R; MS4A2) in 482 subjects from five different regions of Turkey. Genotyping was performed using KASP technology. Turkish data were compared with the haplotype information available from the 1000 Genomes Project Phase 3 (26 human populations from 5 ancestry groups). We did not observe significant differences among Turkish groups. Comparing other ancestries, we identified haplotype similarity of Turkish subjects with European populations in IL13-1L4, IL4R, and ADAM33 loci; and with central Asians in MS4A2 region. Considering loci displaying Turkish-European haplotype similarity (i.e., IL13-1L4, IL4R, and ADAM33), we observed differences between Turkish subjects and northern/western Europeans. Conversely, no significant difference was determined in MS4A2 between Turkish and central Asian populations. Finally, we assessed the haplotypes responsible for the differences between Turkish and European samples and the potential functional effects on the immunogenetic loci investigated. (C) 2016 Elsevier B.V. All rights reserved.Öğe Haplotypic similarity in immunogenes of Turkish population with Europeans and Central Asians(Wiley-Blackwell, 2016) Karaca, Şefayet; Karaca, Mehmet; Civelek, Ersoy; Şekerel, Bülent Enis; Polimanti, Renato[Abstract Not Available]Öğe High prevalence of cerebral venous sinus thrombosis (CVST) as presentation of cystathionine beta-synthase deficiency in childhood: Molecular and clinical findings of Turkish probands(Elsevier Science Bv, 2014) Karaca, Mehmet; Hismi, Burcu; Özgul, Riza Koksal; Karaca, Şefayet; Yılmaz, Didem Yücel; Coşkun, Turgay; Sivri, Hatice Serap; Tokatlı, Ayşegül; Dursun, AliClassical homocystinuria is the most commonly inherited disorder of sulfur metabolism, caused by the genetic alterations in human cystathionine beta-synthase (CBS) gene. In this study, we present comprehensive clinical findings and the genetic basis of homocystinuria in a cohort of Turkish patients. Excluding some CBS mutations, detailed genotype-phenotype correlation for different CBS mutations has not been established in literature. We aimed to make clinical subgroups according to main clinical symptoms and discussed these data together with mutational analysis results from our patients. Totally, 16 different mutations were identified; twelve of which had already been reported, and four are novel (p.N93Y, p.L251P, p.D281V and c.829-2A>T). The probands were classified into three major groups according to the clinical symptoms caused by these mutations. A psychomotor delay was the most common diagnostic symptom (n = 12, 46.2% neurological presentation), followed by thromboembolic events (n = 6, 23.1% vascular presentation) and lens ectopia, myopia or marfanoid features (n = 5, 19.2% connective tissue presentation). Pyridoxine responsiveness was 7.7%; however, with partial responsive probands, the ratio was 53.9%. In addition, five thrombophilic nucleotide changes including MTHFR c.677 C>T and c.1298 A>C, Factor V c.1691 G>A, Factor II c.20210 G>A, and SERPINE1 4G/5G were investigated to assess their contributions to the clinical spectrum. We suggest that the effect of these polymorphisms on clinical phenotype of CBS is not very clear since the distribution of thrombophilic polymorphisms does not differ among specific groups. This study provides molecular findings of 26 Turkish probands with homocystinuria and discusses the clinical presentations and putative effects of the CBS mutations. Crown Copyright (C) 2013 Published by Elsevier B.V. All rights reserved.Öğe Identification of mutations and evaluation of cardiomyopathy in Turkish patients with primary carnitine deficiency(Springer, 2012) Kılıç, M.; ÖzgÜl, R. K.; Coşkun, T.; Yücel, D.; Karaca, Mehmet; Sivri, H. S.; Tokatlı, A.; Şahin, M.; Karagöz, T.; Dursun, A.Primary systemic carnitine deficiency (SCD) is an autosomal recessive disorder caused by defective cellular carnitine transport. Patients usually present with predominant metabolic or cardiac manifestations. SCD is caused by mutations in the organic cation/carnitine transporter OCTN2 (SLC22A5) gene. Mutation analysis of SLC22A5 gene was carried out in eight Turkish patients from six families. Six patients presented with signs and symptoms of heart failure, cardiomyopathy, and low plasma carnitine levels, five of them with concurrent anemia. A patient with dilated cardiomyopathy had also facial dysmorphia, microcephaly, and developmental delay. Tandem MS analyses in siblings of the patients revealed two more cases with low plasma carnitine levels. SCD diagnosis was confirmed in these two cases by mutation screening. These two cases were asymptomatic but echocardiography revealed left ventricular dilatation in one of them. Carnitine treatment was started before the systemic signs and symptoms developed in these patients. Mean value of serum carnitine levels of the patients was 2.63 +/- 1.92 mu mol/L at the time of diagnosis. After 1 year of treatment, carnitine values increased to 16.62 +/- 5.11 (p < 0.001) and all responded to carnitine supplementation clinically. Mutation screening of the OCTN2 gene study in the patients revealed two novel (p.G411V, p.G152R), and four previously identified mutations (p.R254X, p.R282X, p.R289X, p.T337Pfs12X). Early recognition and carnitine supplementation can be lifesaving in this inborn error of fatty acid oxidation.Öğe IDENTIFICATION OF MUTATIONS IN THE PCCA AND PCCB GENES CAUSING PROPIONIC ACIDEMIA IN TURKISH PATIENTS(Springer, 2010) Özgül, R. K.; Yücel, D.; Hismi, B.; Karaca, Mehmet; Sivri, H. S.; Coskun, T.; Tokatlı, A.; Dursun, A.[Abstract Not Available]Öğe International warfarin genotype-guided dosing algorithms in the Turkish population and their preventive effects on major and life-threatening hemorrhagic events(Future Medicine LTD, 2015) Karaca, Şefayet; Bozkurt, Nujen Çolak; Cesuroğlu, Tomris; Karaca, Mehmet; Bozkurt, Mehmet; Eskioğlu, Erdal; Polimanti, RenatoTo determine the accuracy of international warfarin pharmacogenetic algorithms developed on large multiethnic cohorts (comprising more than 1000 subjects) to predict therapeutic warfarin doses in Turkish patients. Materials & methods: We investigated two Turkish warfarin-treated cohorts: patients with no history of hemorrhagic or thromboembolic event and patients with major and life-threatening hemorrhagic events. Results: International pharmacogenetic algorithms showed good performances in predicting the therapeutic dose of patients with no history of bleedings, but they did not significantly detect the incorrect warfarin dose of patients with major and life-threatening hemorrhagic events. Conclusion: Although genetic information can predict the therapeutic warfarin dose, the accuracy of the international pharmacogenetic algorithms is not sufficient to be used for warfarin screening in Turkish patients.Öğe Molecular analysis of homocystinuria in Turkish patients(SPRINGER, 2010) Karaca, Mehmet; Özgül, Rıza Köksal; Dündar, H.; Coşkun, Turgay; Tokatlı, Ayşegül; Sivri, Hatice Serap; Dursun, Ali[Abstract Not Available]Öğe Molecular and structural analysıs of six nonsense mutations in mut methylmalonic acidemia patients including two novel nonsense mutations(SPRINGER, 2010) Dündar, H.; Özgül, Rıza Köksal; Ünal, O.; Karaca, Mehmet; Aydın, H., I; Tokatli, Ayşegül; Sivri, Hatice Serap; Coşkun, Turgay; Dursun, Ali[Abstract Not Available]Öğe Molecular characterisation of biotinidase gene mutations in Turkish patients; an update of the results(SPRINGER, 2012) Karaca, Mehmet; Yucel, D.; Unal, O.; Guzel, A.; Tokatlı, Ayşegül; Coskun, Turgay; Dursun, Ali; Sivri, Hatice Serap[Abstract Not Available]Öğe Mutation analysis in arsb gene in Turkish patients with mps type vı: high prevalence of L321P mutation(SPRINGER, 2011) Özgül, Rıza Köksal; Karaca, Mehmet; Sivri, Hatice; Tokatlı, Ayşegül; Coşkun, Turgay; Dursun, Ali[Abstract Not Available]Öğe Mutation analysis in biotinidase gene by denaturing high pressure liquid chromatography(SPRINGER, 2010) Karaca, Mehmet; Özgül, Rıza Köksal; Güzel, A.; Kılıç, M.; Tokatlı, Ayşegül; Coskun, Turgay; Göksun, E.; Dursun, Ali; Sivri, Hatice Serap[Abstract Not Available]
