Journal ArticleDOI
Genetic insights into common pathways and complex relationships among immune-mediated diseases.
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TLDR
It is revealed that several diseases share multiple susceptibility loci, but there are many nuances that help explain why early evidence of extensive 'sharing' is not always reflected in epidemiological overlap.Abstract:
Shared aetiopathogenic factors among immune-mediated diseases have long been suggested by their co-familiality and co-occurrence, and molecular support has been provided by analysis of human leukocyte antigen (HLA) haplotypes and genome-wide association studies. The interrelationships can now be better appreciated following the genotyping of large immune disease sample sets on a shared SNP array: the 'Immunochip'. Here, we systematically analyse loci shared among major immune-mediated diseases. This reveals that several diseases share multiple susceptibility loci, but there are many nuances. The most associated variant at a given locus frequently differs and, even when shared, the same allele often has opposite associations. Interestingly, risk alleles conferring the largest effect sizes are usually disease-specific. These factors help to explain why early evidence of extensive 'sharing' is not always reflected in epidemiological overlap.read more
Citations
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Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci
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TL;DR: The COMorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity), and the strong comor bid between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease.
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From genome-wide associations to candidate causal variants by statistical fine-mapping.
TL;DR: The strengths and weaknesses of different fine-mapping approaches are reviewed, emphasizing the main factors that affect performance, including integration of trans-ethnic human population data and functional annotations.
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Ankylosing Spondylitis and Axial Spondyloarthritis
TL;DR: The clinical definition of ankylosing spONDylitis and axial spondyloarthritis is summarized, the pathogenesis of these conditions is discussed, and approaches to management are reviewed.
Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity
Lam C. Tsoi,Sarah L. Spain,Jo Knight,Eva Ellinghaus,Philip E. Stuart,Francesca Capon,Jun Ding,Yun Li,Trilokraj Tejasvi,Johann E. Gudjonsson,Hyun Min Kang,Mariet Allen,Ross McManus,Giuseppe Novelli,Lena Samuelsson,J. Schalkwijk,Mona Ståhle,A D Burden,Catherine H. Smith,Michael J. Cork,Xavier Estivill,Anne M. Bowcock,Gerald G. Krueger,Wolfgang Weger,Jane Worthington,Rachid Tazi-Ahnini,Frank O. Nestle,Adrian Hayday,Per Hoffmann,Juliane Winkelmann,Cisca Wijmenga,Cordelia Langford,Sarah Edkins,Ross M. Andrews,H. D. Blackburn,A. Strange,Richard D. Pearson,Damjan Vukcevic,Chris C. A. Spencer,Panagiotis Deloukas,Ulrich Mrowietz,Stefan Schreiber,Stephan Weidinger,Sulev Kõks,Külli Kingo,Tõnu Esko,Andres Metspalu,Henry W. Lim,John J. Voorhees,Michael Weichenthal,H. E. Wichmann,Vinod Chandran,Cheryl F. Rosen,Proton Rahman,Dafna D. Gladman,Christopher E.M. Griffiths,André Reis,Juha Kere,R. P. Nnair,Andre Franke,J. Barker,Gonçalo R. Abecasis,J. T. Eelder,R. Ttrembath,Kristina Callis Duffin,Cynthia Helms,David E. Goldgar,Justin Paschall,Mary J. Malloy,Clive R. Pullinger,John P. Kane,Jennifer M. Gardner,A. Perlmutter,Andrew Miner,Bing Jian Feng,Ravi Hiremagalore,Robert W. Ike,Enno Christophers,Tilo Henseler,Andreas Ruether,Steven J. Schrodi,Sampath Prahalad,Stephen L. Guthery,Judith Fischer,Wilson Liao,Pui-Yan Kwok,Alan Menter,G.M. Lathrop,Carol Wise,Ann B. Begovich,Alexandros Onoufriadis,Michael E. Weale,Anne C. Hofer,Wolfgang Salmhofer,Philip A. Wolf,Kati Kainu,Ulpu Saarialho-Kere,Sari Suomela,P. Badorf,Ulrike Hüffmeier,Werner Kurrat,Wolfgang Küster,Jesús Lascorz,Rotraut Mössner,Funda Schürmeier-Horst,Markward Ständer,Horst Traupe,Judith G.M. Bergboer,Martin den Heijer,P.C.M. van de Kerkhof,Patrick L.J.M. Zeeuwen,L. Barnes,Linda E. Campbell,Caitriona Cusack,C. M. Coleman,Judith Conroy,Sean Ennis,Oliver FitzGerald,Phil Gallagher,Alan D. Irvine,Brian Kirby,Trevor Markham,Whi McLean,Joseph McPartlin,Sarah Rogers,Anthony W. Ryan,Agnieszka Zawirska,Emiliano Giardina,Tiziana Lepre,Carlo Perricone,Gemma Martin-Ezquerra,Ramon M. Pujol,Eva Riveira-Muñoz,Annica Inerot,Åsa Torinsson Naluai,Lotus Mallbris,Katarina Wolk,Joyce Leman,Anne Barton,Richard B. Warren,Helen S. Young,Isis Ricaño-Ponce,Gosia Trynka,Fawnda Pellett,A. Henschel,M. Aurand,Bruce F. Bebo,Christian Gieger,Thomas Illig,Susanne Moebus,K. H. Jöckel,Raimund Erbel,Peter Donnelly,Leena Peltonen,Jenefer M. Blackwell,Elvira Bramon,Matthew A. Brown,Juan P. Casas,Aiden Corvin,N. Craddock,Audrey Duncanson,Janusz Jankowski,Hugh S. Markus,Christopher G. Mathew,Mark I. McCarthy,Colin N. A. Palmer,Robert Plomin,Anna Rautanen,Stephen Sawcer,Nilesh J. Samani,Ananth C. Viswanathan,Nicholas W. Wood,Céline Bellenguez,Colin Freeman,Garrett Hellenthal,Eleni Giannoulatou,Matti Pirinen,Zhan Su,Sarah E. Hunt,R. Gwilliam,Suzannah Bumpstead,Serge Dronov,Matthew W. Gillman,Erin Gray,Naomi Hammond,Alagurevathi Jayakumar,O. T. McCann,Jennifer Liddle,Maritza Pérez,Simon C. Potter,Radhi Ravindrarajah,Michelle Ricketts,Matthew Waller,Paul A. Weston,Sara Widaa,Pamela Whittaker,R. P. Neir,J.N.W.N. Barker,James T. Elder,Richard C. Trembath +199 more
TL;DR: A meta-analysis of genome-wide association studies and independent data sets genotyped on the Immunochip identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals, and identified five independent signals within previously known loci.
Journal ArticleDOI
Immunometabolic pathways in BCG-induced trained immunity
Rob J.W. Arts,Agostinho Carvalho,Claudia La Rocca,Carla Palma,Fernando Rodrigues,Ricardo Silvestre,Johanneke Kleinnijenhuis,Ekta Lachmandas,Luís G. Gonçalves,Ana Belinha,Cristina Cunha,Marije Oosting,Leo A. B. Joosten,Giuseppe Matarese,Reinout van Crevel,Mihai G. Netea +15 more
TL;DR: It is shown that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans.
References
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Journal ArticleDOI
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Journal ArticleDOI
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TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
Journal Article
An integrated encyclopedia of DNA elements in the human genome.
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Journal ArticleDOI
Finding the missing heritability of complex diseases
Teri A. Manolio,Francis S. Collins,Nancy J. Cox,David Goldstein,Lucia A. Hindorff,David J. Hunter,Mark I. McCarthy,Erin M. Ramos,Lon R. Cardon,Aravinda Chakravarti,Judy H. Cho,Alan E. Guttmacher,Augustine Kong,Leonid Kruglyak,Leonid Kruglyak,Elaine R. Mardis,Charles N. Rotimi,Montgomery Slatkin,David Valle,Alice S. Whittemore,Michael Boehnke,Andrew G. Clark,Evan E. Eichler,Greg Gibson,Jonathan L. Haines,Trudy F. C. Mackay,Steven A. McCarroll,Peter M. Visscher +27 more
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Journal ArticleDOI
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease
Jean-Pierre Hugot,Mathias Chamaillard,Mathias Chamaillard,Habib Zouali,Suzanne Lesage,Jean-Pierre Cézard,Jacques Belaiche,Sven Almer,Curt Tysk,Colm O'Morain,Miquel A. Gassull,Vibeke Binder,Yigael Finkel,Antoine Cortot,Robert Modigliani,Pierre Laurent-Puig,C. Gower-Rousseau,J. Macry,Jean-Frederic Colombel,Mourad Sahbatou,Gilles Thomas,Gilles Thomas +21 more
TL;DR: It is suggested that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn’s disease that can now be further investigated.
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