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Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles.
LHA - Leipzig Health Atlas

Abstract (Expand)

INTRODUCTION: Autoinflammatory and autoimmune disorders are characterized by aberrant changes in innate and adaptive immunity that may lead from an initial inflammatory state to an organ specific damage. … These disorders possess heterogeneity in terms of affected organs and clinical phenotypes. However, despite the differences in etiology and phenotypic variations, they share genetic associations, treatment responses and clinical manifestations. The mechanisms involved in their initiation and development remain poorly understood, however the existence of some clear similarities between autoimmune and autoinflammatory disorders indicates variable degrees of interaction between immune-related mechanisms. METHODS: Our study aims at contributing to a holistic, pathway-centered view on the inflammatory condition of autoimmune and autoinflammatory diseases. We have evaluated similarities and specificities of pathway activity changes in twelve autoimmune and autoinflammatory disorders by performing meta-analysis of publicly available gene expression datasets generated from peripheral blood mononuclear cells, using a bioinformatics pipeline that integrates Self Organizing Maps and Pathway Signal Flow algorithms along with KEGG pathway topologies. RESULTS AND CONCLUSIONS: The results reveal that clinically divergent disease groups share common pathway perturbation profiles. We identified pathways, similarly perturbed in all the studied diseases, such as PI3K-Akt, Toll-like receptor, and NF-kappa B signaling, that serve as integrators of signals guiding immune cell polarization, migration, growth, survival and differentiation. Further, two clusters of diseases were identified based on specifically dysregulated pathways: one gathering mostly autoimmune and the other mainly autoinflammatory diseases. Cluster separation was driven not only by apparent involvement of pathways implicated in adaptive immunity in one case, and inflammation in the other, but also by processes not explicitly related to immune response, but rather representing various events related to the formation of specific pathophysiological environment. Thus, our data suggest that while all of the studied diseases are affected by activation of common inflammatory processes, disease-specific variations in their relative balance are also identified.

Authors: A. Arakelyan, L. Nersisyan, D. Poghosyan, L. Khondkaryan, A. Hakobyan, H. Loffler-Wirth, E. Melanitou, H. Binder

Date Published: 4th Nov 2017

Publication Type: Not specified

Association analysis identifies 65 new breast cancer risk loci
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer … risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P \textless 5 \times 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Authors: Kyriaki Michailidou, Sara Lindström, Joe Dennis, Jonathan Beesley, Shirley Hui, Siddhartha Kar, Audrey Lemaçon, Penny Soucy, Dylan Glubb, Asha Rostamianfar, Manjeet K. Bolla, Qin Wang, Jonathan Tyrer, Ed Dicks, Andrew Lee, Zhaoming Wang, Jamie Allen, Renske Keeman, Ursula Eilber, Juliet D. French, Xiao Qing Chen, Laura Fachal, Karen McCue, Amy E. McCart Reed, Maya Ghoussaini, Jason S. Carroll, Xia Jiang, Hilary Finucane, Marcia Adams, Muriel A. Adank, Habibul Ahsan, Kristiina Aittomäki, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Banu Arun, Paul L. Auer, François Bacot, Myrto Barrdahl, Caroline Baynes, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Judith S. Brand, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Louise Brinton, Per Broberg, Ian W. Brock, Annegien Broeks, Angela Brooks-Wilson, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Katja Butterbach, Qiuyin Cai, Hui Cai, Trinidad Caldés, Federico Canzian, Angel Carracedo, Brian D. Carter, Jose E. Castelao, Tsun L. Chan, Ting-Yuan David Cheng, Kee Seng Chia, Ji-Yeob Choi, Hans Christiansen, Christine L. Clarke, Margriet Collée, Don M. Conroy, Emilie Cordina-Duverger, Sten Cornelissen, David G. Cox, Angela Cox, Simon S. Cross, Julie M. Cunningham, Kamila Czene, Mary B. Daly, Peter Devilee, Kimberly F. Doheny, Thilo Dörk, Isabel Dos-Santos-Silva, Martine Dumont, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Mingajeva Elvira, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Valerie Gaborieau, Marike Gabrielson, Manuela Gago-Dominguez, Yu-Tang Gao, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Gord Glendon, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Nathalie Hamel, Susan Hankinson, Patricia Harrington, Steven N. Hart, Jaana M. Hartikainen, Mikael Hartman, Alexander Hein, Jane Heyworth, Belynda Hicks, Peter Hillemanns, Dona N. Ho, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Ming-Feng Hou, Chia-Ni Hsiung, Guanmengqian Huang, Keith Humphreys, Junko Ishiguro, Hidemi Ito, Motoki Iwasaki, Hiroji Iwata, Anna Jakubowska, Wolfgang Janni, Esther M. John, Nichola Johnson, Kristine Jones, Michael Jones, Arja Jukkola-Vuorinen, Rudolf Kaaks, Maria Kabisch, Katarzyna Kaczmarek, Daehee Kang, Yoshio Kasuga, Michael J. Kerin, Sofia Khan, Elza Khusnutdinova, Johanna I. Kiiski, Sung-Won Kim, Julia A. Knight, Veli-Matti Kosma, Vessela N. Kristensen, Ute Krüger, Ava Kwong, Diether Lambrechts, Loic Le Marchand, Eunjung Lee, Min Hyuk Lee, Jong Won Lee, Chuen Neng Lee, Flavio Lejbkowicz, Jingmei Li, Jenna Lilyquist, Annika Lindblom, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jirong Long, Artitaya Lophatananon, Jan Lubinski, Craig Luccarini, Michael P. Lux, Edmond S. K. Ma, Robert J. MacInnis, Tom Maishman, Enes Makalic, Kathleen E. Malone, Ivana Maleva Kostovska, Arto Mannermaa, Siranoush Manoukian, JoAnn E. Manson, Sara Margolin, Shivaani Mariapun, Maria Elena Martinez, Keitaro Matsuo, Dimitrios Mavroudis, James McKay, Catriona McLean, Hanne Meijers-Heijboer, Alfons Meindl, Primitiva Menéndez, Usha Menon, Jeffery Meyer, Hui Miao, Nicola Miller, Nur Aishah Mohd Taib, Kenneth Muir, Anna Marie Mulligan, Claire Mulot, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Sune F. Nielsen, Dong-Young Noh, Børge G. Nordestgaard, Aaron Norman, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Curtis Olswold, Nick Orr, V. Shane Pankratz, Sue K. Park, Tjoung-Won Park-Simon, Rachel Lloyd, Jose I. A. Perez, Paolo Peterlongo, Julian Peto, Kelly-Anne Phillips, Mila Pinchev, Dijana Plaseska-Karanfilska, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Elizabeth Pugh, Katri Pylkäs, Brigitte Rack, Paolo Radice, Nazneen Rahman, Gadi Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Jane Romm, Kathryn J. Ruddy, Thomas Rüdiger, Anja Rudolph, Matthias Ruebner, Emiel J. T. Rutgers, Emmanouil Saloustros, Dale P. Sandler, Suleeporn Sangrajrang, Elinor J. Sawyer, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Fredrick Schumacher, Peter Schürmann, Rodney J. Scott, Christopher Scott, Sheila Seal, Caroline Seynaeve, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Grace Sheng, Mark E. Sherman, Martha J. Shrubsole, Xiao-Ou Shu, Ann Smeets, Christof Sohn, Melissa C. Southey, John J. Spinelli, Christa Stegmaier, Sarah Stewart-Brown, Jennifer Stone, Daniel O. Stram, Harald Surowy, Anthony Swerdlow, Rulla Tamimi, Jack A. Taylor, Maria Tengström, Soo H. Teo, Mary Beth Terry, Daniel C. Tessier, Somchai Thanasitthichai, Kathrin Thöne, Rob A. E. M. Tollenaar, Ian Tomlinson, Ling Tong, Diana Torres, Thérèse Truong, Chiu-Chen Tseng, Shoichiro Tsugane, Hans-Ulrich Ulmer, Giske Ursin, Michael Untch, Celine Vachon, Christi J. van Asperen, David van den Berg, Ans M. W. van den Ouweland, Lizet van der Kolk, Rob B. van der Luijt, Daniel Vincent, Jason Vollenweider, Quinten Waisfisz, Shan Wang-Gohrke, Clarice R. Weinberg, Camilla Wendt, Alice S. Whittemore, Hans Wildiers, Walter Willett, Robert Winqvist, Alicja Wolk, Anna H. Wu, Lucy Xia, Taiki Yamaji, Xiaohong R. Yang, Cheng Har Yip, Keun-Young Yoo, Jyh-Cherng Yu, Wei Zheng, Ying Zheng, Bin Zhu, Argyrios Ziogas, Elad Ziv, Sunil R. Lakhani, Antonis C. Antoniou, Arnaud Droit, Irene L. Andrulis, Christopher I. Amos, Fergus J. Couch, Paul D. P. Pharoah, Jenny Chang-Claude, Per Hall, David J. Hunter, Roger L. Milne, Montserrat García-Closas, Marjanka K. Schmidt, Stephen J. Chanock, Alison M. Dunning, Stacey L. Edwards, Gary D. Bader, Georgia Chenevix-Trench, Jacques Simard, Peter Kraft, Douglas F. Easton

Date Published: 1st Nov 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Effect of a multifaceted educational intervention for anti-infectious measures on sepsis mortality: a cluster randomized trial
SepNet - German Competence Network Sepsis

Abstract (Expand)

PURPOSE Guidelines recommend administering antibiotics within 1 h of sepsis recognition but this recommendation remains untested by randomized trials. This trial was set up to investigate whether …r survival is improved by reducing the time before initiation of antimicrobial therapy by means of a multifaceted intervention in compliance with guideline recommendations. METHODS The MEDUSA study, a prospective multicenter cluster-randomized trial, was conducted from July 2011 to July 2013 in 40 German hospitals. Hospitals were randomly allocated to receive conventional continuous medical education (CME) measures (control group) or multifaceted interventions including local quality improvement teams, educational outreach, audit, feedback, and reminders. We included 4183 patients with severe sepsis or septic shock in an intention-to-treat analysis comparing the multifaceted intervention (n = 2596) with conventional CME (n = 1587). The primary outcome was 28-day mortality. RESULTS The 28-day mortality was 35.1% (883 of 2596 patients) in the intervention group and 26.7% (403 of 1587 patients; p = 0.01) in the control group. The intervention was not a risk factor for mortality, since this difference was present from the beginning of the study and remained unaffected by the intervention. Median time to antimicrobial therapy was 1.5 h (interquartile range 0.1-4.9 h) in the intervention group and 2.0 h (0.4-5.9 h; p = 0.41) in the control group. The risk of death increased by 2% per hour delay of antimicrobial therapy and 1% per hour delay of source control, independent of group assignment. CONCLUSIONS Delay in antimicrobial therapy and source control was associated with increased mortality but the multifaceted approach was unable to change time to antimicrobial therapy in this setting and did not affect survival.

Authors: Frank Bloos, Hendrik Rüddel, Daniel Thomas-Rüddel, Daniel Schwarzkopf, Christine Pausch, Stephan Harbarth, Torsten Schreiber, Matthias Gründling, John Marshall, Philipp Simon, Mitchell M. Levy, Manfred Weiss, Andreas Weyland, Herwig Gerlach, Tobias Schürholz, Christoph Engel, Claudia Matthäus-Krämer, Christian Scheer, Friedhelm Bach, Reimer Riessen, Bernhard Poidinger, Karin Dey, Norbert Weiler, Andreas Meier-Hellmann, Helene H. Häberle, Gabriele Wöbker, Udo X. Kaisers, Konrad Reinhart

Date Published: 1st Nov 2017

Publication Type: Journal article

Human Diseases: disease by infectious agent

ATP2C2 and DYX1C1 are putative modulators of dyslexia-related MMR
Genetical Statistics and Systems Biology

Abstract (Expand)

Background Dyslexia is a specific learning disorder affecting reading and spelling abilities. Its prevalence is ~5% in German-speaking individuals. Although the etiology of dyslexia largely remains to …o be determined, comprehensive evidence supports deficient phonological processing as a major contributing factor. An important prerequisite for phonological processing is auditory discrimination and, thus, essential for acquiring reading and spelling skills. The event-related potential Mismatch Response (MMR) is an indicator for auditory discrimination capabilities with dyslexics showing an altered late component of MMR in response to auditory input. Methods In this study, we comprehensively analyzed associations of dyslexia-specific late MMRs with genetic variants previously reported to be associated with dyslexia-related phenotypes in multiple studies comprising 25 independent single-nucleotide polymorphisms (SNPs) within 10 genes. Results First, we demonstrated validity of these SNPs for dyslexia in our sample by showing that additional inclusion of a polygenic risk score improved prediction of impaired writing compared with a model that used MMR alone. Secondly, a multifactorial regression analysis was conducted to uncover the subset of the 25 SNPs that is associated with the dyslexia-specific late component of MMR. In total, four independent SNPs within DYX1C1 and ATP2C2 were found to be associated with MMR stronger than expected from multiple testing. To explore potential pathomechanisms, we annotated these variants with functional data including tissue-specific expression analysis and eQTLs. Conclusion Our findings corroborate the late component of MMR as a potential endophenotype for dyslexia and support tripartite relationships between dyslexia-related SNPs, the late component of MMR and dyslexia.

Authors: Bent Müller, Gesa Schaadt, Johannes Boltze, Frank Emmrich, Michael A. Skeide, Nicole E. Neef, Indra Kraft, Jens Brauer, Angela D. Friederici, Holger Kirsten, Arndt Wilcke

Date Published: 1st Nov 2017

Publication Type: Journal article

Growth and Final Height Among Children With Phenylketonuria
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND OBJECTIVES Growth is an important criterion to evaluate health in childhood and adolescence, especially in patients depending on special dietary treatment. Phenylketonuria (PKU) is the …e most common inherited disease of amino acid metabolism. Patients with PKU depend on a special phenylalanine-restricted diet, low in natural protein. The study aimed to evaluate growth, growth rate, and target height in 224 patients with PKU. METHODS Retrospective, longitudinal analysis of standardized, yearly measurements of height, weight, and calculated growth rate (SD score [SDS]) of patients with PKU aged 0 to 18 years were conducted by using the national computerized CrescNet database. Inclusion was restricted to patients carried to term with a confirmed diagnosis of PKU or mild hyperphenylalaninemia determined by newborn screening and early treatment initiation. RESULTS From birth to adulthood, patients with PKU were significantly shorter than healthy German children (height SDS at 18 years: -0.882 \pm 0.108, P \textless .001). They missed their target height by 3 cm by adulthood (women: P = .02) and 5 cm (men: P = .01). In patients receiving casein hydrolysate during childhood, this was more pronounced compared with patients receiving amino acid mixtures (P \textless .001). Growth rate was significantly reduced during their first 2 years of life and in puberty (growth rate SDS: -1.1 to -0.5 m/year, P \textless .001 and -0.5; P \textless .02). CONCLUSIONS Early diagnosed, treated, and continuously monitored patients with PKU showed reduced height from birth onward. During the last 2 decades, this phenomenon attenuated, probably because of advances in PKU therapy related to protein supplements and special low-protein foods.

Authors: Alena G. Thiele, Ruth Gausche, Cornelia Lindenberg, Christoph Beger, Maria Arelin, Carmen Rohde, Ulrike Mütze, Johannes F. Weigel, Klaus Mohnike, Christoph Baerwald, Markus Scholz, Wieland Kiess, Roland Pfäffle, Skadi Beblo

Date Published: 1st Nov 2017

Publication Type: Journal article

Association between lipoprotein(a) level and type 2 diabetes: no evidence for a causal role of lipoprotein(a) and insulin
Genetical Statistics and Systems Biology

Abstract (Expand)

AIMS Inverse relationships have been described between the largely genetically determined levels of serum/plasma lipoprotein(a) [Lp(a)], type 2 diabetes (T2D) and fasting insulin. Here, we aimed to …o evaluate the nature of these relationships with respect to causality. METHODS We tested whether we could replicate the recent negative findings on causality between Lp(a) and T2D by employing the Mendelian randomization (MR) approach using cross-sectional data from three independent cohorts, Berlin Aging Study II (BASE-II; n = 2012), LIFE-Adult (n = 3281) and LIFE-Heart (n = 2816). Next, we explored another frequently discussed hypothesis in this context: Increasing insulin levels during the course of T2D disease development inhibits hepatic Lp(a) synthesis and thereby might explain the inverse Lp(a)-T2D association. We used two fasting insulin-associated variants, rs780094 and rs10195252, as instrumental variables in MR analysis of n = 4937 individuals from BASE-II and LIFE-Adult. We further investigated causality of the association between fasting insulin and Lp(a) by combined MR analysis of 12 additional SNPs in LIFE-Adult. RESULTS While an Lp(a)-T2D association was observed in the combined analysis (meta-effect of OR [95% CI] = 0.91 [0.87-0.96] per quintile, p = 1.3x10(-4)), we found no evidence of causality in the Lp(a)-T2D association (p = 0.29, fixed effect model) when using the variant rs10455872 as the instrumental variable in the MR analyses. Likewise, no evidence of a causal effect of insulin on Lp(a) levels was found. CONCLUSIONS While these results await confirmation in larger cohorts, the nature of the inverse Lp(a)-T2D association remains to be elucidated.

Authors: Nikolaus Buchmann, Markus Scholz, Christina M. Lill, Ralph Burkhardt, Rahel Eckardt, Kristina Norman, Markus Loeffler, Lars Bertram, Joachim Thiery, Elisabeth Steinhagen-Thiessen, Ilja Demuth

Date Published: 1st Nov 2017

Publication Type: Journal article

The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: A randomized controlled trial
SepNet - German Competence Network Sepsis

Abstract (Expand)

OBJECTIVE We report on the effect of hemoadsorption therapy to reduce cytokines in septic patients with respiratory failure. METHODS This was a randomized, controlled, open-label, multicenter trial. …al. Mechanically ventilated patients with severe sepsis or septic shock and acute lung injury or acute respiratory distress syndrome were eligible for study inclusion. Patients were randomly assigned to either therapy with CytoSorb hemoperfusion for 6 hours per day for up to 7 consecutive days (treatment), or no hemoperfusion (control). Primary outcome was change in normalized IL-6-serum concentrations during study day 1 and 7. RESULTS 97 of the 100 randomized patients were analyzed. We were not able to detect differences in systemic plasma IL-6 levels between the two groups (n = 75; p = 0.15). Significant IL-6 elimination, averaging between 5 and 18% per blood pass throughout the entire treatment period was recorded. In the unadjusted analysis, 60-day-mortality was significantly higher in the treatment group (44.7%) compared to the control group (26.0%; p = 0.039). The proportion of patients receiving renal replacement therapy at the time of enrollment was higher in the treatment group (31.9%) when compared to the control group (16.3%). After adjustment for patient morbidity and baseline imbalances, no association of hemoperfusion with mortality was found (p = 0.19). CONCLUSIONS In this patient population with predominantly septic shock and multiple organ failure, hemoadsorption removed IL-6 but this did not lead to lower plasma IL-6-levels. We did not detect statistically significant differences in the secondary outcomes multiple organ dysfunction score, ventilation time and time course of oxygenation.

Authors: Dirk Schädler, Christine Pausch, Daniel Heise, Andreas Meier-Hellmann, Jörg Brederlau, Norbert Weiler, Gernot Marx, Christian Putensen, Claudia Spies, Achim Jörres, Michael Quintel, Christoph Engel, John A. Kellum, Martin K. Kuhlmann

Date Published: 30th Oct 2017

Publication Type: Journal article

Human Diseases: disease by infectious agent

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