IRAK-M is involved in the pathogenesis of early-onset persistent asthma.
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.
Balaci
Lenuta
L
Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Cagliari, Onserrato, Italy.
Spada
Maria Cristina
MC
Olla
Nazario
N
Sole
Gabriella
G
Loddo
Laura
L
Anedda
Francesca
F
Naitza
Silvia
S
Zuncheddu
Maria Antonietta
MA
Maschio
Andrea
A
Altea
Daniele
D
Uda
Manuela
M
Pilia
Sabrina
S
Sanna
Serena
S
Masala
Marco
M
Crisponi
Laura
L
Fattori
Matilde
M
Devoto
Marcella
M
Doratiotto
Silvia
S
Rassu
Stefania
S
Mereu
Simonetta
S
Giua
Enrico
E
Cadeddu
Natalina Graziella
NG
Atzeni
Roberto
R
Pelosi
Umberto
U
Corrias
Adriano
A
Perra
Roberto
R
Torrazza
Pier Luigi
PL
Pirina
Pietro
P
Ginesu
Francesco
F
Marcias
Silvano
S
Schintu
Maria Grazia
MG
Del Giacco
Gennaro Sergio
GS
Manconi
Paolo Emilio
PE
Malerba
Giovanni
G
Bisognin
Andrea
A
Trabetti
Elisabetta
E
Boner
Attilio
A
Pescollderungg
Lydia
L
Pignatti
Pier Franco
PF
Schlessinger
David
D
Cao
Antonio
A
Pilia
Giuseppe
G
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
D005819:Genetic Markers; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases