title: IRAK-M is involved in the pathogenesis of early-onset persistent 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- 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.
authors.affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Cagliari, Onserrato, Italy.
authors.forename: Lenuta
authors.initials: L
authors.lastname: Balaci
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Spada
authors.forename: Nazario
authors.initials: N
authors.lastname: Olla
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sole
authors.forename: Laura
authors.initials: L
authors.lastname: Loddo
authors.forename: Francesca
authors.initials: F
authors.lastname: Anedda
authors.forename: Silvia
authors.initials: S
authors.lastname: Naitza
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Zuncheddu
authors.forename: Andrea
authors.initials: A
authors.lastname: Maschio
authors.forename: Daniele
authors.initials: D
authors.lastname: Altea
authors.forename: Manuela
authors.initials: M
authors.lastname: Uda
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pilia
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.forename: Marco
authors.initials: M
authors.lastname: Masala
authors.forename: Laura
authors.initials: L
authors.lastname: Crisponi
authors.forename: Matilde
authors.initials: M
authors.lastname: Fattori
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.forename: Silvia
authors.initials: S
authors.lastname: Doratiotto
authors.forename: Stefania
authors.initials: S
authors.lastname: Rassu
authors.forename: Simonetta
authors.initials: S
authors.lastname: Mereu
authors.forename: Enrico
authors.initials: E
authors.lastname: Giua
authors.forename: Natalina Graziella
authors.initials: NG
authors.lastname: Cadeddu
authors.forename: Roberto
authors.initials: R
authors.lastname: Atzeni
authors.forename: Umberto
authors.initials: U
authors.lastname: Pelosi
authors.forename: Adriano
authors.initials: A
authors.lastname: Corrias
authors.forename: Roberto
authors.initials: R
authors.lastname: Perra
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Torrazza
authors.forename: Pietro
authors.initials: P
authors.lastname: Pirina
authors.forename: Francesco
authors.initials: F
authors.lastname: Ginesu
authors.forename: Silvano
authors.initials: S
authors.lastname: Marcias
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Schintu
authors.forename: Gennaro Sergio
authors.initials: GS
authors.lastname: Del Giacco
authors.forename: Paolo Emilio
authors.initials: PE
authors.lastname: Manconi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Malerba
authors.forename: Andrea
authors.initials: A
authors.lastname: Bisognin
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Trabetti
authors.forename: Attilio
authors.initials: A
authors.lastname: Boner
authors.forename: Lydia
authors.initials: L
authors.lastname: Pescollderungg
authors.forename: Pier Franco
authors.initials: PF
authors.lastname: Pignatti
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.forename: Antonio
authors.initials: A
authors.lastname: Cao
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pilia
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000483:Alleles; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D001249:Asthma / Q000175:diagnosis / Q000453:epidemiology* / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D015331:Cohort Studies; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics* / Q000378:metabolism; D007558:Italy / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008126:Lod Score; D008168:Lung / Q000378:metabolism / Q000601:surgery; D008297:Male; D018895:Microsatellite Repeats; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D035781:Siblings
chemical_list: D005819:Genetic Markers; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases