IRAK-M is involved in the pathogenesis of early-onset persistent asthma by 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, Boner Attilio, Pescollderungg Lydia, Pignatti Pier Franco, Schlessinger David, Cao Antonio, Pilia Giuseppe in American journal of human genetics (2007). PubMed

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- kappa B 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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