XXXX , a regulator of the @entity2533 pathway, is associated with severe otitis media in Western Australian @entity1 .

@entity1 @entity2172 @entity19 @entity2536 @entity39591 @entity22213 @entity2533 @entity1594 @entity11280
@entity2172 ( @entity2172 ) is a common childhood disease characterised by @entity2172 following infection. Susceptibility to recurrent acute @entity2172 (rAOM) and chronic @entity2172 with effusion (COME) is highly heritable. Two @entity19 mutants, Junbo and Jeff, spontaneously develop severe @entity2172 with similar phenotypes to @entity1 disease. Fine-mapping of these mutants identified two genes ( @entity22213 and @entity39591 ) that interact with the @entity2533 ( @entity2533 ) signalling pathway. We investigated these genes, as well as four @entity11280 (SMAD) genes of the @entity2533 pathway, as candidate rAOM/COME susceptibility genes in two predominantly Caucasian populations. Single-nucleotide polymorphisms (SNPs) within @entity39591 (family-based association testing Z-Score=2.61; P(best)=0.009) were associated with severe @entity2172 in family-based analysis of 434 families (561 affected individuals) from the Western Australian Family Study of @entity2172 . The @entity39591 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 @entity22213 variants. Family-based associations at @entity2536 (P=0.038) and @entity1594 (P=0.048) were not replicated. Together, these data provide strong evidence for @entity39591 as a susceptibility gene for severe @entity2172 .
