@incollection{Lutz1991,
  author    = {Lutz, Werner K.},
  title     = {Dose-response relationships in chemical carcinogenesis: from DNA adducts to tumor incidence},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-71625},
  publisher      = {Universit{\"a}t W{\"u}rzburg},
  year      = {1991},
  abstract  = {Mechanistic possibilitles responsible for nonlinear shapes of the dose-response relationship in chemical carcinogenesis are discussed. (i) Induction and saturation of enzymatic activation and detoxification processes and of DNA repair affect the relationship between dose and steady-state DNA adduct Ievel; (ii) The fixation of DNA adducts in the form of mutations is accelerated by stimulation of the cell division, for Jnstance due to regenerative hyperplasia at cytotoxic dose Ievels; (iii) The rate of tumor formation results from a superposition of the rates of the individual steps. It can become exponential with dose if more than one step is accelerated by the DNA damage exerted by the genotoxic carcinogen. The strongly sigmoidal shapes often observed for dose-tumor incidence relationships in animal bioassays supports this analysis. A power of four for the dose in the su~linear part of the curve is the maximum observed (formaldehyde). In contrast to animal experiments, epidemiological data ln humans rarely show a slgnificant deviation from linearity. The discrepancy might be explained by the fact that a I arge nu mber of genes contribute to the overall sensitivity of an individual and to the respective heterogeneity within the human population. Mechanistic nonlinearities are flattened out in the presence of genetic and life-style factors which affect the sensitivity for the development of cancer. For a risk assessment, linear extrapolation from the high-dose lncidence to the spontaneaus rate can therefore be approprlate in a heterogeneous population even if the mechanism of action would result in a nonlinear shape of the dose-response curve in a homogeneaus population.},
  language  = {en}
}
@phdthesis{Amschler2010,
  author    = {Amschler, Katharina},
  title     = {Sensibilisierung von Melanomzellen gegen{\"u}ber Zytostatika durch zwei verschiedene Mechanismen der NF-kB-Inhibition},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-56342},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {Die vorliegende Arbeit zeigt eine M{\"o}glichkeit auf, die bisher meist erfolglose Chemotherapie des malignen Melanoms zu verbessern: Durch Inhibition des Transkriptionsfaktors NF-kB, der f{\"u}r die Regulation vieler tumorrelevanter Gene verantwortlich ist, konnten die Tumorzellen gegen{\"u}ber der Wirkung von Zytostatika sensibilisiert werden. Zun{\"a}chst wurden acht verschiedene Melanomzellen in Bezug auf ihre NF-kB-Aktivit{\"a}t und der Expression NF-kB-regulierter Proteine vergleichen. Es konnte gezeigt werden, dass die Mehrzahl der Melanomzellen {\"u}ber konstitutive Aktivit{\"a}t von NF-κB verf{\"u}gt. Dabei bestand kein eindeutiger Zusammenhang zwischen der Expression NF-kB-regulierter Proteine und der Aktivit{\"a}t dieses Transkriptionsfaktors im Kern, was komplexe Regulationsmechanismen bei der Transkription und Translation vermuten l{\"a}sst. Anhand einer ausgew{\"a}hlten Melanomzelllinie konnte gezeigt werden, dass zwei verschiedene NF-kB-Inhibitoren, der Proteasom-Inhibitor Bortezomib und der neue IKK-Inhibitor KINK-1 die Aktivit{\"a}t von NF-kB deutlich hemmen. Beim Vergleich beider NF-kB-Inhibitoren ließen sich unerwartet verschiedene molekulare Wirkungsmechanismen nachweisen: W{\"a}hrend Bortezomib konzentrationsabh{\"a}ngig eine sehr starke Induktion von NOXA, eine Induktion von p53 sowie eine Abnahme von Cyclin D1 bewirkte, zeigte KINK-1 seine Effekte vor allem in der Reduktion von Chemokinen wie IL-8 und MCP-1. Passend zur Ver{\"a}nderung der Expression zellzyklus-relevanter Proteine hatte Bortezomib einen st{\"a}rkeren Effekt auf den Zellzyklus als KINK-1. Beide Inhibitoren wurden mit verschiedenen Zytostatika kombiniert und konnten einerseits die Apoptoseinduktion durch Zytostatika verst{\"a}rken und andererseits die durch Zytostatika reduzierte Invasion weiter reduzieren. Allerdings zeigte sich bei der Untersuchung tumorrelevanter Chemokine, dass KINK-1 im Gegensatz zu Bortezomib synergistische Effekte mit Camptothecin und Doxorubicin aufweist. Trotz molekularer Unterschiede bewirkten beide NF-kB-Inhibitoren vergleichbare funktionelle Effekte auf zellul{\"a}rer Ebene. Dies galt auch f{\"u}r ein pr{\"a}klinisches in-vivo-Modell, in dem die experimentelle Lungenmetastasierung von B16F10-Melanomzellen in M{\"a}usen ermittelt wurde: Hier wurden die M{\"a}use mit Camptothecin, KINK-1 und Bortezomib allein im Vergleich zu den jeweiligen Kombinationen aus Zytostatikum und NF-kB-Inhibitor behandelt. Beide Kombinationen zeigten eine signifikante Reduktion des Lungengewichts im Vergleich zu Camptothecin allein. Diese Arbeit konnte also den Nutzen aus NF-kB-Inhibition in Kombination mit Zytostatika f{\"u}r die hier verwendeten Substanzen bekr{\"a}ftigen und dabei einige molekulare Unterschiede aufdecken.},
  subject      = {Apoptosis},
  language  = {de}
}
@article{GrassmannFritscheKeilhaueretal.2012,
  author    = {Grassmann, Felix and Fritsche, Lars G. and Keilhauer, Claudia N. and Heid, Iris M. and Weber, Bernhard H. F.},
  title     = {Modelling the Genetic Risk in Age-Related Macular Degeneration},
  series = {PLoS One},
  volume    = {7},
  journal   = {PLoS One},
  number    = {5},
  doi       = {10.1371/journal.pone.0037979},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131315},
  pages     = {e37979},
  year      = {2012},
  abstract  = {Late-stage age-related macular degeneration (AMD) is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS) for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC) of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95\% CI: 1.69-2.05) than patients aged 75 and above (1.45, 95\% CI: 1.36-1.54). Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95\% CI: 14.11-1131.96) for individuals in the highest category (GRS 3.44-5.18, 0.5\% of the general population) compared to subjects with the most common genetic background (GRS -0.05-1.70, 40.2\% of general population). The highest GRS category identifies AMD patients with a sensitivity of 7.9\% and a specificity of 99.9\% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4\% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2\% of individuals in the two lowest GRS categories which represent almost 50\% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available.},
  language  = {en}
}
@article{KlinglerHeiderichGirardetal.2014,
  author    = {Klingler, Werner and Heiderich, Sebastian and Girard, Thierry and Gravino, Elvira and Heffron, James J. A. and Johannsen, Stephan and Jurkat-Rott, Karin and R{\"u}ffert, Henrik and Schuster, Frank and Snoeck, Marc and Sorrentino, Vincenzo and Tegazzin, Vincenzo and Lehmann-Horn, Frank},
  title     = {Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study},
  series = {Orphanet Journal of Rare Diseases},
  volume    = {9},
  journal   = {Orphanet Journal of Rare Diseases},
  number    = {8},
  issn      = {1750-1172},
  doi       = {10.1186/1750-1172-9-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117630},
  year      = {2014},
  abstract  = {Background: Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The molecular basis of MH is excessive release of Ca2+ in skeletal muscle principally by a mutated ryanodine receptor type 1 (RyR1). To identify factors explaining the variable phenotypic presentation and complex pathomechanism, we analyzed proven MH events in terms of clinical course, muscle contracture, genetic factors and pharmocological triggers. Methods: In a multi-centre study including seven European MH units, patients with a history of a clinical MH episode confirmed by susceptible (MHS) or equivocal (MHE) in vitro contracture tests (IVCT) were investigated. A test result is considered to be MHE if the muscle specimens develop pathological contractures in response to only one of the two test substances, halothane or caffeine. Crises were evaluated using a clinical grading scale (CGS), results of IVCT and genetic screening. The effects of SCh and volatile anesthetics on Ca2+ release from sarcoplasmic reticulum (SR) were studied in vitro. Results: A total of 200 patients met the inclusion criteria. Two MH crises (1\%) were triggered by SCh (1 MHS, 1 MHE), 18\% by volatile anesthetics and 81\% by a combination of both. Patients were 70\% male and 50\% were younger than 12 years old. Overall, CGS was in accord with IVCT results. Crises triggered by enflurane had a significantly higher CGS compared to halothane, isoflurane and sevoflurane. Of the 200 patients, 103 carried RyR1 variants, of which 14 were novel. CGS varied depending on the location of the mutation within the RyR1 gene. In contrast to volatile anesthetics, SCh did not evoke Ca2+ release from isolated rat SR vesicles. Conclusions: An MH event could depend on patient-related risk factors such as male gender, young age and causative RyR1 mutations as well as on the use of drugs lowering the threshold of myoplasmic Ca2+ release. SCh might act as an accelerant by promoting unspecific Ca2+ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.},
  language  = {en}
}
@article{MitchellMacarthurGanetal.2014,
  author    = {Mitchell, Anna L. and Macarthur, Katie D. R. and Gan, Earn H. and Baggott, Lucy E. and Wolff, Anette S. B. and Skinningsrud, Beate and Platt, Hazel and Short, Andrea and Lobell, Anna and Kampe, Olle and Bensing, Sophie and Betterle, Corrado and Kasperlik-Zaluska, Anna and Zurawek, Magdalena and Fichna, Marta and Kockum, Ingrid and Eriksson, Gabriel Nordling and Ekwall, Olov and Wahlberg, Jeanette and Dahlqvist, Per and Hulting, Anna-Lena and Penna-Martinez, Marissa and Meyer, Gesine and Kahles, Heinrich and Badenhoop, Klaus and Hahner, Stephanie and Quinkler, Marcus and Falorni, Alberto and Phipps-Green, Amanda and Merriman, Tony R. and Ollier, William and Cordell, Heather J. and Undlien, Dag and Czarnocka, Barbara and Husebye, Eystein and Pearce, Simon H. S.},
  title     = {Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {3},
  doi       = {10.1371/journal.pone.0088991},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117105},
  pages     = {e88991},
  year      = {2014},
  abstract  = {Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-kappa B1 and IL23A genes in the UK and Italian cohorts respectively. Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.},
  language  = {en}
}
@article{BleinBardelDanjeanetal.2015,
  author    = {Blein, Sophie and Bardel, Claire and Danjean, Vincent and McGuffog, Lesley and Healay, Sue and Barrowdale, Daniel and Lee, Andrew and Dennis, Joe and Kuchenbaecker, Karoline B. and Soucy, Penny and Terry, Mary Beth and Chung, Wendy K. and Goldgar, David E. and Buys, Saundra S. and Janavicius, Ramunas and Tihomirova, Laima and Tung, Nadine and Dorfling, Cecilia M. and van Rensburg, Elizabeth J. and Neuhausen, Susan L. and Ding, Yuan Chun and Gerdes, Anne-Marie and Ejlertsen, Bent and Nielsen, Finn C. and Hansen, Thomas V. O. and Osorio, Ana and Benitez, Javier and Andreas Conejero, Raquel and Segota, Ena and Weitzel, Jeffrey N. and Thelander, Margo and Peterlongo, Paolo and Radice, Paolo and Pensotti, Valeria and Dolcetti, Riccardo and Bonanni, Bernardo and Peissel, Bernard and Zaffaroni, Daniela and Scuvera, Giulietta and Manoukian, Siranoush and Varesco, Liliana and Capone, Gabriele L. and Papi, Laura and Ottini, Laura and Yannoukakos, Drakoulis and Konstantopoulou, Irene and Garber, Judy and Hamann, Ute and Donaldson, Alan and Brady, Angela and Brewer, Carole and Foo, Claire and Evans, D. Gareth and Frost, Debra and Eccles, Diana and Douglas, Fiona and Cook, Jackie and Adlard, Julian and Barwell, Julian and Walker, Lisa and Izatt, Louise and Side, Lucy E. and Kennedy, M. John and Tischkowitz, Marc and Rogers, Mark T. and Porteous, Mary E. and Morrison, Patrick J. and Platte, Radka and Eeles, Ros and Davidson, Rosemarie and Hodgson, Shirley and Cole, Trevor and Godwin, Andrew K and Isaacs, Claudine and Claes, Kathleen and De Leeneer, Kim and Meindl, Alfons and Gehrig, Andrea and Wappenschmidt, Barbara and Sutter, Christian and Engel, Christoph and Niederacher, Dieter and Steinemann, Doris and Plendl, Hansjoerg and Kast, Karin and Rhiem, Kerstin and Ditsch, Nina and Arnold, Norbert and Varon-Mateeva, Raymonda and Schmutzler, Rita K. and Preisler-Adams, Sabine and Markov, Nadja Bogdanova and Wang-Gohrke, Shan and de Pauw, Antoine and Lefol, Cedrick and Lasset, Christine and Leroux, Dominique and Rouleau, Etienne and Damiola, Francesca and Dreyfus, Helene and Barjhoux, Laure and Golmard, Lisa and Uhrhammer, Nancy and Bonadona, Valerie and Sornin, Valerie and Bignon, Yves-Jean and Carter, Jonathan and Van Le, Linda and Piedmonte, Marion and DiSilvestro, Paul A. and de la Hoya, Miguel and Caldes, Trinidad and Nevanlinna, Heli and Aittom{\"a}ki, Kristiina and Jager, Agnes and van den Ouweland, Ans M. W. and Kets, Carolien M. and Aalfs, Cora M. and van Leeuwen, Flora E. and Hogervorst, Frans B. L. and Meijers-Heijboer, Hanne E. J. and Oosterwijk, Jan C. and van Roozendaal, Kees E. P. and Rookus, Matti A. and Devilee, Peter and van der Luijt, Rob B. and Olah, Edith and Diez, Orland and Teule, Alex and Lazaro, Conxi and Blanco, Ignacio and Del Valle, Jesus and Jakubowska, Anna and Sukiennicki, Grzegorz and Gronwald, Jacek and Spurdle, Amanda B. and Foulkes, William and Olswold, Curtis and Lindor, Noralene M. and Pankratz, Vernon S. and Szabo, Csilla I. and Lincoln, Anne and Jacobs, Lauren and Corines, Marina and Robson, Mark and Vijai, Joseph and Berger, Andreas and Fink-Retter, Anneliese and Singer, Christian F. and Rappaport, Christine and Geschwantler Kaulich, Daphne and Pfeiler, Georg and Tea, Muy-Kheng and Greene, Mark H. and Mai, Phuong L. and Rennert, Gad and Imyanitov, Evgeny N. and Mulligan, Anna Marie and Glendon, Gord and Andrulis, Irene L. and Tchatchou, Andrine and Toland, Amanda Ewart and Pedersen, Inge Sokilde and Thomassen, Mads and Kruse, Torben A. and Jensen, Uffe Birk and Caligo, Maria A. and Friedman, Eitan and Zidan, Jamal and Laitman, Yael and Lindblom, Annika and Melin, Beatrice and Arver, Brita and Loman, Niklas and Rosenquist, Richard and Olopade, Olufunmilayo I. and Nussbaum, Robert L. and Ramus, Susan J. and Nathanson, Katherine L. and Domchek, Susan M. and Rebbeck, Timothy R. and Arun, Banu K. and Mitchell, Gillian and Karlan, Bethy Y. and Lester, Jenny and Orsulic, Sandra and Stoppa-Lyonnet, Dominique and Thomas, Gilles and Simard, Jacques and Couch, Fergus J. and Offit, Kenenth and Easton, Douglas F. and Chenevix-Trench, Georgia and Antoniou, Antonis C. and Mazoyer, Sylvie and Phelan, Catherine M. and Sinilnikova, Olga M. and Cox, David G.},
  title     = {An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers},
  series = {Breast Cancer Research},
  volume    = {17},
  journal   = {Breast Cancer Research},
  number    = {61},
  doi       = {10.1186/s13058-015-0567-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145458},
  year      = {2015},
  abstract  = {Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95\% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95\% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.},
  language  = {en}
}
@article{BiernackaSangkuhlJenkinsetal.2015,
  author    = {Biernacka, J. M. and Sangkuhl, K. and Jenkins, G. and Whaley, R. M. and Barman, P. and Batzler, A. and Altman, R. B. and Arolt, V. and Brockm{\"o}ller, J. and Chen, C. H. and Domschke, K. and Hall-Flavin, D. K. and Hong, C. J. and Illi, A. and Ji, Y. and Kampman, O. and Kinoshita, T. and Leinonen, E. and Liou, Y. J. and Mushiroda, T. and Nonen, S. and Skime, M. K. and Wang, L. and Baune, B. T. and Kato, M. and Liu, Y. L. and Praphanphoj, V. and Stingl, J. C. and Tsai, S. J. and Kubo, M. and Klein, T. E. and Weinshilboum, R.},
  title     = {The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response},
  series = {Translational Psychiatry},
  volume    = {5},
  journal   = {Translational Psychiatry},
  number    = {e553},
  doi       = {10.1038/tp.2015.47},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143223},
  year      = {2015},
  abstract  = {Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50\% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N = 2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P = 5.03E - 08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.},
  language  = {en}
}
@article{LupianezVillaescusaCarvalhoetal.2016,
  author    = {Lupia{\~n}ez, Carmen B. and Villaescusa, Maria T. and Carvalho, Agostinho and Springer, Jan and Lackner, Michaela and S{\´a}nchez-Maldonado, Jos{\´e} M. and Canet, Luz M. and Cunha, Cristina and Segura-Catena, Joana and Alcazar-Fuoli, Laura and Solano, Carlos and Fianchi, Luana and Pagano, Livio and Potenza, Leonardo and Aguado, Jos{\´e} M. and Luppi, Mario and Cuenca-Estrella, Manuel and Lass-Fl{\"o}rl, Cornelia and Einsele, Hermann and V{\´a}zquez, Lourdes and R{\´i}os-Tamayo, Rafael and Loeffler, J{\"u}rgen and Jurado, Manuel and Sainz, Juan},
  title     = {Common Genetic Polymorphisms within NF kappa B-Related Genes and the Risk of Developing Invasive Aspergillosis},
  series = {Frontiers in Microbiology},
  volume    = {7},
  journal   = {Frontiers in Microbiology},
  number    = {1243},
  doi       = {10.3389/fmicb.2016.01243},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165209},
  year      = {2016},
  abstract  = {Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4rs12203592T/T genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95\%CI 1.25-31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA.},
  language  = {en}
}