IRAK-M is involved in the pathogenesis of early-onset persistent asthma.
Lenuta Balaci,Maria Cristina Spada,Nazario Olla,Gabriella Sole,Laura Loddo,Francesca Anedda,Silvia Naitza,Maria Antonietta Zuncheddu,Andrea Maschio,Daniele Altea,Manuela Uda,Sabrina Pilia,Serena Sanna,Marco Masala,Laura Crisponi,Matilde Fattori,Marcella Devoto,Marcella Devoto,Silvia Doratiotto,Stefania Rassu,Simonetta Mereu,Enrico Giua,Natalina Graziella Cadeddu,Roberto Atzeni,Umberto Pelosi,Adriano Corrias,Roberto Perra,Pier Luigi Torrazza,Pietro Pirina,Francesco Ginesu,Silvano Marcias,Maria Grazia Schintu,Gennaro Sergio Del Giacco,Paolo Emilio Manconi,Giovanni Malerba,Andrea Bisognin,Elisabetta Trabetti,Attilio Boner,Lydia Pescollderungg,Pier Franco Pignatti,David Schlessinger,Antonio Cao,Giuseppe Pilia +42 more
TLDR
The data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma.Abstract:
Asthma is a multifactorial disease influenced by genetic and environmental factors In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24 We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF-κB and inflammation Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthmaread more
Citations
More filters
Journal ArticleDOI
A large-scale, consortium-based genomewide association study of asthma.
Miriam F. Moffatt,Ivo Gut,Florence Demenais,David P. Strachan,Emmanuelle Bouzigon,Simon Heath,Erika von Mutius,Martin Farrall,Mark Lathrop,William O.C.M. Cookson +9 more
TL;DR: A few common alleles are associated with disease risk at all ages and suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation in asthma.
Supplementary materials to a paper "A large-scale, consortium-based genomewide association study of asthma"
Moffatt Mf,Gut Ig,F. Demenais,Strachan Dp,E. Bouzigon,S. Heath,A. Kumar,P. Burney,D. Jarvis,M. Wjst,M. Kogevinas,R. Jogi,C. Janson,Franklin Ka,E. Omenaas,B. Leynaert,I. Pin,J. Heinrich,Probst Hensch Nm,Anto Jm,J. Sunyer,Maldonado Ja,J. Martinez Moratalla,I. Urrutia,F. Payo,F. Kauffmann,Dizier Mh,V. Siroux,A. Boznanski,C. Braun Fahrländer,J. Genuneit,J. Glas,E. Horak,M. Kabesch,Pillai Sg,Helms Pj,K. Carlsen,Carlsen Kh,J. Gerritsen,M. Silverman,P. Sly,J. Tsanakas,A. Von Berg,M. Whyte,M. Blumenthal,M. Imboden,T. Rochat,Thun Ga,Gerbase Mw,I. Curjuric,Gaspoz Jm,Liu Lj,Wouters Im,T. Sigsgaard,D. Heederik,I. Basinas,V. Schlunssen,Ø. Omland,P. Cullinan,R. Vermeulen,J. Henderson,R. Granell,McArdle Wl,Smith Gd,James Al,J. Hui,Palmer Lj,J. Beilby,Musk Aw,C. Laprise,Hudson Tj,M. Lemire,D. Daley,A. Becker,M. Chan Yeung,A. Sandford,Kozyrskyj Al,P. Paré,A. Ferguson,H. Dimich Ward,Watson Wt,Freidin Mb,Bragina EIu,Deev Ia,Deeva Ev,Kobyakova Os,Puzyrev Vp,Ogorodova Lm,Khusnutdinova Ek,Karunas As,Fedorova Yy,Hall Ip,I. Sayers,Tobin Md,Wan Yi,Heaney Lg,Al Momani Ba,Mansur Ah,S. Manney,Thomson Nc,R. Chaudhuri,Brightling Ce,M. Bafadhel,A. Singapuri,R. Niven,A. Simpson,Holloway Jw,Howarth Ph,Polonikov Av,Ivanov Vp,Solodilova Ma,E. Melén,G. Pershagen,A. Bergström,I. Kull,F. Nyberg,M. Wickman,C. Söderhäll,J. Kere,Postma Ds,M. Kerkhof,B. Brunekreef,Smit Ha,de Jongste Jc,A. Wijga,Aalberse Rc,Hoekstra Mo,Koppelman Gh,A. Binia,Chung Kf,P. Bhavsar,F. Chow,P. Macedo,A. Menzies Gow,N. van Stiphout,A. Bush,Lee Ya,J. Esparza Gordillo,R. Nickel,U. Wahn,S. Lau,I. Marenholz,T. Haahtela,L. von Hertzen,P. Jousilahti,T. Laatikainen,Mäkelä Mj,E. Vartiainen,T. Laitinen,Balding Dj,Peden Jf,E. Corda,D. Lechner,C. Besse,D. Zelenika,A. Boland,D. Bacq,S. Demonchy,H. Blanche,Y. Kamatani,E. von Mutius,M. Farrall,M. Lathrop,Cookson Wo +163 more
Journal ArticleDOI
Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity
Sadia Saeed,Jessica Quintin,Hindrik H. D. Kerstens,Nagesha A.S. Rao,Ali Aghajanirefah,Filomena Matarese,Shih-Chin Cheng,Jacqueline M. Ratter,Kim Berentsen,Martijn van der Ent,Nilofar Sharifi,Eva M. Janssen-Megens,Menno ter Huurne,Amit Mandoli,Tom van Schaik,Aylwin Ng,Aylwin Ng,Frances Burden,Kate Downes,Mattia Frontini,Vinod Kumar,Evangelos J. Giamarellos-Bourboulis,Willem H. Ouwehand,Jos W. M. van der Meer,Leo A. B. Joosten,Cisca Wijmenga,Joost H.A. Martens,Ramnik J. Xavier,Ramnik J. Xavier,Colin Logie,Mihai G. Netea,Hendrik G. Stunnenberg +31 more
TL;DR: The epigenetic and transcriptional programs of monocyte differentiation to macrophages that distinguish tolerant and trained macrophage phenotypes are uncovered, providing a resource to further understand and manipulate immune-mediated responses.
Journal ArticleDOI
Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease
TL;DR: This approach is already suggesting entirely novel pathways to disease-eg, alternative macrophage specification, steroid refractory innate immunity, the interleukin-17-regulatory T-cell axis, epidermal growth factor receptor co-amplification, and Th2-mimicking but non-T-cell,interleukins 18 and 33 dependent processes that can offer unexpected therapeutic opportunities for specific patient endotypes.
Journal ArticleDOI
MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins.
Yuanjia Tang,Xiaobing Luo,Huijuan Cui,Xuming Ni,Min Yuan,Yanzhi Guo,Xinfang Huang,Haibo Zhou,Niek de Vries,Paul P. Tak,Shunle Chen,Nan Shen +11 more
TL;DR: Investigation of the contribution of microRNA-146a, identified in the pilot expression profiling step, to the pathogenesis of systemic lupus erythematosus revealed a negative regulator of innate immunity, which provides potential novel strategies for therapeutic intervention.
References
More filters
Journal ArticleDOI
Inference of population structure using multilocus genotype data
TL;DR: Pritch et al. as discussed by the authors proposed a model-based clustering method for using multilocus genotype data to infer population structure and assign individuals to populations, which can be applied to most of the commonly used genetic markers, provided that they are not closely linked.
Journal ArticleDOI
Haploview: analysis and visualization of LD and haplotype maps
TL;DR: Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Journal ArticleDOI
Toll-like receptor signalling
Shizuo Akira,Kiyoshi Takeda +1 more
TL;DR: Rapid progress that has recently improved the understanding of the molecular mechanisms that mediate TLR signalling is reviewed.
Journal ArticleDOI
The global burden of asthma: executive summary of the GINA Dissemination Committee Report
TL;DR: This report provides a wealth of information that will be an invaluable source of information for those who wish to explore available data on the burden of asthma by region and will be extremely useful to develop background materials for World Asthma Day activities in 2004 and well into the future.
Journal Article
Parametric and nonparametric linkage analysis: a unified multipoint approach.
TL;DR: It is shown that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric linkage analysis, and appears to be the method of choice for pedigree studies of complex traits.
Related Papers (5)
IRAK-M is a negative regulator of toll-like receptor signaling
Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness
Paul Van Eerdewegh,Randall D. Little,Josée Dupuis,Richard G. Del Mastro,Kathy Falls,Jason Simon,Dana Torrey,Sunil Pandit,Joyce McKenny,Karen Braunschweiger,Alison Walsh,Ziying Liu,Brooke Hayward,Colleen Folz,Susan P. Manning,Alicia Bawa,Lisa Saracino,Michelle Thackston,Youssef Benchekroun,Neva J. Capparell,Mei Wang,Ron Adair,Yun Feng,Joann Dubois,Michael Fitzgerald,Hui Huang,Rene Gibson,Kristina Allen,Alex Pedan,Melvyn R. Danzig,Shelby P. Umland,Robert W. Egan,Cuss Francis M,S. Rorke,Joanne B. Clough,John W. Holloway,Stephen T. Holgate,Tim Keith +37 more
Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma
Miriam F. Moffatt,Michael Kabesch,Liming Liang,Anna L. Dixon,David P. Strachan,Simon Heath,Martin Depner,Andrea von Berg,Albrecht Bufe,Ernst Rietschel,Andrea Heinzmann,Burkard Simma,Thomas Frischer,Saffron A.G. Willis-Owen,Kenny C. C. Wong,Thomas Illig,Christian Vogelberg,Stephan K. Weiland,Erika von Mutius,Gonçalo R. Abecasis,Martin Farrall,Ivo Gut,G. Mark Lathrop,William O.C.M. Cookson +23 more
Characterization of a common susceptibility locus for asthma-related traits
Tarja Laitinen,Anne Polvi,Pia Rydman,Johanna Vendelin,Ville Pulkkinen,Paula Salmikangas,Siru Mäkelä,Marko Rehn,Asta Pirskanen,Anna Rautanen,Marco Zucchelli,Harriet Gullstén,Harriet Gullstén,Marina Leino,Harri Alenius,Tuula Petäys,Tari Haahtela,Annika Laitinen,Catherine Laprise,Thomas J. Hudson,Lauri A. Laitinen,Juha Kere,Juha Kere +22 more