Browsing by Subject "Disease association"

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    Application of the RIMARC algorithm to a large data set of action potentials and clinical parameters for risk prediction of atrial fibrillation
    (Springer, 2015) Ravens, U.; Katircioglu-Öztürk, D.; Wettwer, E.; Christ, T.; Dobrev, D.; Voigt, N.; Poulet, C.; Loose, S.; Simon, J.; Stein, A.; Matschke, K.; Knaut, M.; Oto, E.; Oto, A.; Güvenir, H. A.
    Ex vivo recorded action potentials (APs) in human right atrial tissue from patients in sinus rhythm (SR) or atrial fibrillation (AF) display a characteristic spike-and-dome or triangular shape, respectively, but variability is huge within each rhythm group. The aim of our study was to apply the machine-learning algorithm ranking instances by maximizing the area under the ROC curve (RIMARC) to a large data set of 480 APs combined with retrospectively collected general clinical parameters and to test whether the rules learned by the RIMARC algorithm can be used for accurately classifying the preoperative rhythm status. APs were included from 221 SR and 158 AF patients. During a learning phase, the RIMARC algorithm established a ranking order of 62 features by predictive value for SR or AF. The model was then challenged with an additional test set of features from 28 patients in whom rhythm status was blinded. The accuracy of the risk prediction for AF by the model was very good (0.93) when all features were used. Without the seven AP features, accuracy still reached 0.71. In conclusion, we have shown that training the machine-learning algorithm RIMARC with an experimental and clinical data set allows predicting a classification in a test data set with high accuracy. In a clinical setting, this approach may prove useful for finding hypothesis-generating associations between different parameters.
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    Circulating LL37 targets plasma extracellular vesicles to immune cells and intensifies Behçet's disease severity
    (Taylor and Francis, 2017-02) Kahraman, T.; Gucluler, G.; Simsek, I.; Yagci, F. C.; Yildirim, M.; Ozen, C.; Dinc, A.; Gursel, M.; Ikromzoda, L.; Sutlu, T.; Gay, S.; Gursel, I.
    Behçet's disease (BD) activity is characterised by sustained, over-exuberant immune activation, yet the underlying mechanisms leading to active BD state are poorly defined. Herein, we show that the human cathelicidin derived antimicrobial peptide LL37 associates with and directs plasma extracellular vesicles (EV) to immune cells, thereby leading to enhanced immune activation aggravating BD pathology. Notably, disease activity was correlated with elevated levels of circulating LL37 and EV plasma concentration. Stimulation of healthy PBMC with active BD patient EVs induced heightened IL1β, IFNα, IL6 and IP10 secretion compared to healthy and inactive BD EVs. Remarkably, when mixed with LL37, healthy plasma-EVs triggered a robust immune activation replicating the pathology inducing properties of BD EVs. The findings of this study could be of clinical interest in the management of BD, implicating LL37/EV association as one of the major contributors of BD pathogenesis.
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    Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1
    (American Association for Cancer Research, 1999) Ricciardone, M. D.; Özçelik, T.; Cevher, B.; Özdaǧ, H.; Tuncer, M.; Gürgey, A.; Uzunalimoǧlu, O.; Çetinkaya, H.; Tanyeli, A.; Erken, E.; Öztürk, M.
    Heterozygous germ-line mutations in the DNA mismatch repair genes lead to hereditary nonpolyposis colorectal cancer. The disease susceptibility of individuals who constitutionally lack both wild-type alleles is unknown. We have identified three offspring in a hereditary nonpolyposis colorectal cancer family who developed hematological malignancy at a very early age, and at least two of them displayed signs of neurofibromatosis type 1 (NF1). DNA sequence analysis and allele-specific amplification in two siblings revealed a homozygous MLH1 mutation (C676T → Arg226Stop). Thus, a homozygous germ- line MLH1 mutation and consequent mismatch repair deficiency results in a mutator phenotype characterized by leukemia and/or lymphoma associated with neurofibromatosis type 1.
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    An integrated map of structural variation in 2,504 human genomes
    (Nature Publishing Group, 2015) Sudmant, P. H.; Rausch, T.; Gardner, E. J.; Handsaker, R. E.; Abyzov, A.; Huddleston, J.; Zhang, Y.; Ye, K.; Jun, G.; Fritz, M. Hsi-Yang; Konkel, M. K.; Malhotra, A.; Stütz, A. M.; Shi, X.; Casale, F. P.; Chen, J.; Hormozdiari, F.; Dayama, G.; Chen, K.; Malig, M.; Chaisson, M. J. P.; Walter, K.; Meiers, S.; Kashin, S.; Garrison, E.; Auton, A.; Lam, H. Y. K.; Mu, X. J.; Alkan, C.; Antaki, D.; Bae, T.; Cerveira, E.; Chines, P.; Chong, Z.; Clarke, L.; Dal, E.; Ding, L.; Emery, S.; Fan, X.; Gujral, M.; Kahveci, F.; Kidd, J. M.; Kong, Y.; Lameijer, Eric-Wubbo; McCarthy, S.; Flicek, P.; Gibbs, R. A.; Marth, G.; Mason, C. E.; Menelaou, A.; Muzny, D. M.; Nelson, B. J.; Noor, A.; Parrish, N. F.; Pendleton, M.; Quitadamo, A.; Raeder, B.; Schadt, E. E.; Romanovitch, M.; Schlattl, A.; Sebra, R.; Shabalin, A. A.; Untergasser, A.; Walker J. A.; Wang, M.; Yu, F.; Zhang, C.; Zhang, J.; Zheng-Bradley, X.; Zhou, W.; Zichner, T.; Sebat, J.; Batzer, M. A.; McCarroll, S. A.; Mills, R. E.; Gerstein, M. B.; Bashir, A.; Stegle, O.; Devine, S. E.; Lee, C.; Eichler, E. E.; Korbel, J. O.
    Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.
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    Lack of association between RNASEL Arg462Gln variant and the risk of breast cancer
    (International Institute of Anticancer Research, 2004) Sevinç, A.; Yannoukakos, D.; Konstantopoulou, I.; Manguoglu, E.; Lüleci, G.; Çolak, T.; Akyerli, C.; Çolakoglu, G.; Tez, M.; Sayek, I.; Gerassimos, V.; Nasioulas, G.; Papadopoulou, E.; Florentin, L.; Kontogianni, E.; Bozkurt, B.; Kocabas, N. A.; Karakaya, A. E.; Yulug, I. G.; Özçelik, T.
    Background: The RNASEL G1385A variant was recently found to be implicated in the development of prostate cancer. Considering the function of RNase L and the pleiotropic effects of mutations associated with cancer, we sought to investigate whether the RNASEL G1385A variant is a risk factor for breast cancer. Patients and Methods: A total of 453 breast cancer patients and 382 age- and sex-matched controls from Greece and Turkey were analyzed. Genotyping for the RNASEL G1385A variant was performed using an Amplification Refractory Mutation System (ARMS). Results: Statistical evaluation of the RNASEL G1385A genotype distribution among breast cancer patients and controls revealed no significant association between the presence of the risk genotype and the occurrence of breast cancer. Conclusion: Although an increasing number of studies report an association between the RNASEL G1385A variant and prostate cancer risk, this variant does not appear to be implicated in the development of breast cancer.
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    MDM2 T309G polymorphism is associated with bladder cancer
    (International Institute of Anticancer Research, 2006) Onat, O. E.; Tez, M.; Özçelik, T.; Törüner, G. A.
    Recently, a functional T to G polymorphism at nucleotide 309 in the promoter region of the MDM2 gene (rs: 2279744, SNP 309) has been identified. This polymorphism has an impact on the expression of the MDM2 gene, which is a key negative regulator of the tumor suppressor molecule p53. The effect of T309G polymorphism of the MDM2 gene on bladder cancer susceptibility was investigated in a case-control study of 75 bladder cancer patients and 103 controls from Turkey. The G/G genotype exhibited an increased risk of 2.68 (95% CI, 1.34-5.40) for bladder cancer compared with the combination of low-risk genotypes T/T and T/G at this locus. These results show an association between MDM2 T309G polymorphism and bladder cancer in our study group. To the best of our knowledge, this is the first study reporting that MDM2 T309G polymorphism may be a potential genetic susceptibility factor for bladder cancer.
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    MEFV gene is a probable susceptibility gene for Behçet's disease
    (Taylor & Francis, 2005) Imirzalıoglu, N.; Dursun, A.; Tastan, B.; Soysal, Y.; Yakıcıer, M. C.
    Objective: Behçet's disease (BD) is a rare, chronic, multisystem inflammatory disorder. The prevalence of BD is higher in the Middle Eastern and Mediterranean populations. Another chronic inflammatory disease, familial Mediterranean fever (FMF), is also known to be highly prevalent in these populations. The prevalence of BD is higher in the FMF patient population than in populations known to be rich in BD. Both BD and FMF have some pathophysiological features in common and they result from inappropriate activation of neutrophils. Clinical manifestations of both diseases can mimic each other and the coexistence of both diseases in the same patient has been reported. Given that BD and FMF have similar pathophysiological, epidemiological, and clinical features, we hypothesized that the gene responsible for FMF, MEFV, may also play a role in the pathogenesis of BD. Methods: Forty-two BD patients who had no symptoms and family history for FMF and 66 healthy controls were screened for common MEFV gene mutations (E148Q, M680I, M694V, and V726A). Results: Fifteen patients (36%) displayed MEFV mutations (nine M694V, five E148Q, and one M680I) and mutation rates were significantly elevated compared to 66 (11%) healthy controls (p=0.0034). Conclusion: The occurrence of frequent MEFV mutations in BD patients suggests that the MEFV gene is involved in the pathogenesis of Behçet's disease. © 2005 Taylor & Francis.
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    Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy
    (Nature Publishing, 2002) Topçu, M.; Akyerli, C.; Sayi, A.; Törüner, G. A.; Koçoǧlu, S. R.; Cimbiş, M.; Özçelik, T.
    Rett syndrome is a severe neurodevelopmental disorder that arises from mutations in the X-linked MECP2 gene. It is almost exclusively seen in girls due to the predominant occurrence of the mutations on the paternal X-chromosome, and also the early postnatal lethal effect of the disease causing mutations in hemizygous boys. We identified a boy with features of classic Rett syndrome who is mosaic for the truncating MECP2 mutation R270X. Chromosome analysis showed normal karyotype. These results indicate that a MECP2 mutation associated with Rett syndrome in females could lead to a similar phenotype in males as a result of somatic mosaicism.
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    X chromosome inactivation and female predisposition to autoimmunity
    (Springer New York, 2008) Ozcelik, T.
    [No abstract available]