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IRAK-M is involved in the pathogenesis of early-onset persistent asthma |
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| Authors: | Balaci Lenuta Spada Maria Cristina Olla Nazario Sole Gabriella Loddo Laura Anedda Francesca Naitza Silvia Zuncheddu Maria Antonietta Maschio Andrea Altea Daniele Uda Manuela Pilia Sabrina Sanna Serena Masala Marco Crisponi Laura Fattori Matilde Devoto Marcella Doratiotto Silvia Rassu Stefania Mereu Simonetta Giua Enrico Cadeddu Natalina Graziella Atzeni Roberto Pelosi Umberto Corrias Adriano Perra Roberto Torrazza Pier Luigi Pirina Pietro Ginesu Francesco Marcias Silvano Schintu Maria Grazia Del Giacco Gennaro Sergio Manconi Paolo Emilio Malerba Giovanni Bisognin Andrea Trabetti Elisabetta |
| Institution: | a Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche Monserrato, Italy b Dipartimento di Scienze e Tecnologie Biomediche, Sezione Patologia Sperimentale c Dipartimento di Scienze Biomediche e Biotecnologie d Dipartimento di Scienze Pediatriche, Allergologia Pediatrica, I Clinica Pediatrica e Università di Cagliari, II Divisione Pneumologia, Ospedale Binaghi f Dipartimento Chirurgico Materno Infantile, Scienza delle Immagini, Sezione Pediatria, Ospedale Macciotta, Istituto Nazionale Riposo e Cura Anziani Policlinico Universitario di Cagliari, Cagliari, Italy g Medicina Interna II Policlinico Universitario di Cagliari, Cagliari, Italy h Allergologia ed Immunologia Clinica Policlinico Universitario di Cagliari, Cagliari, Italy i Clinica Pneumotisiologica, Sassari, Italy j Presidio Pneumotisiologico, Oristano, Italy k The Children's Hospital of Philadelphia, Division of Human Genetics, and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia l Dipartimento di Medicina Sperimentale e Patologia, Università La Sapienza, Roma m Unità Operativa di Allergologia, Ospedale “Cesare Zonchello,” Nuoro, Italy n Dipartimento Materno Infantile e Biologia-Genetica, Sezione di Biologia e Genetica o Clinica Pediatrica (A. Boner), Università di Verona, Verona, Italy p Dipartimento di Pediatria, Ospedale di Bolzano, Bolzano, Italy q and Laboratory of Genetics, National Institute on Aging, Baltimore |
| 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 asthma. |
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