title: FBXO11, a regulator of the TGFβ pathway, is associated with severe otitis media in Western Australian children.
abstract: Otitis media (OM) is a common childhood disease characterised by middle ear inflammation following infection. Susceptibility to recurrent acute OM (rAOM) and chronic OM with effusion (COME) is highly heritable. Two murine mutants, Junbo and Jeff, spontaneously develop severe OM with similar phenotypes to human disease. Fine-mapping of these mutants identified two genes (Evi1 and Fbxo11) that interact with the transforming growth factor β (TGFβ) signalling pathway. We investigated these genes, as well as four Sma- and Mad-related (SMAD) genes of the TGFβ pathway, as candidate rAOM/COME susceptibility genes in two predominantly Caucasian populations. Single-nucleotide polymorphisms (SNPs) within FBXO11 (family-based association testing Z-Score=2.61; P(best)=0.009) were associated with severe OM in family-based analysis of 434 families (561 affected individuals) from the Western Australian Family Study of OM. The FBXO11 association was replicated by directed analysis of Illumina 660W-Quad Beadchip data available for 253 cases and 866 controls (OR=1.55 (95% CI 1.28-1.89); P(best)=6.9 × 10(-6)) available within the Western Australian Pregnancy Cohort (Raine) Study. Combined primary and replication results show P(combined)=2.98 × 10(-6). Neither cohort showed an association with EVI1 variants. Family-based associations at SMAD2 (P=0.038) and SMAD4 (P=0.048) were not replicated. Together, these data provide strong evidence for FBXO11 as a susceptibility gene for severe OM.
authors.affiliation: Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: M S
authors.initials: MS
authors.lastname: Rye
authors.forename: S P
authors.initials: SP
authors.lastname: Wiertsema
authors.forename: E S H
authors.initials: ES
authors.lastname: Scaman
authors.forename: J
authors.initials: J
authors.lastname: Oommen
authors.forename: W
authors.initials: W
authors.lastname: Sun
authors.forename: R W
authors.initials: RW
authors.lastname: Francis
authors.forename: W
authors.initials: W
authors.lastname: Ang
authors.forename: C E
authors.initials: CE
authors.lastname: Pennell
authors.forename: D
authors.initials: D
authors.lastname: Burgner
authors.forename: P
authors.initials: P
authors.lastname: Richmond
authors.forename: S
authors.initials: S
authors.lastname: Vijayasekaran
authors.forename: H L
authors.initials: HL
authors.lastname: Coates
authors.forename: S D
authors.initials: SD
authors.lastname: Brown
authors.forename: J M
authors.initials: JM
authors.lastname: Blackwell
authors.forename: S E
authors.initials: SE
authors.lastname: Jamieson
mesh_terms: D000483:Alleles; D001315:Australia; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D000074008:MDS1 and EVI1 Complex Locus Protein; D010033:Otitis Media / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D011519:Proto-Oncogenes / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C457579:FBXO11 protein, human; D011484:Protein-Arginine N-Methyltransferases