Association of the FBXO11 Gene With Chronic Otitis Media With Effusion and Recurrent Otitis Media

Abstract

The FBXO11 gene is the human homologue of the gene mutated in the novel deaf mouse mutant jeff (Jf), a single gene model of otitis media. We have evaluated single nucleotide polymorphisms (SNPs) in the FBXO11 gene for association with chronic otitis media with effusion/recurrent otitis media (COME/ROM).Design: A total of 13 SNPs were genotyped across the 98.7 kilobases of genomic DNA encompassing FBXO11. Data were analyzed for single SNP association using generalized estimating equations, and haplotypes were evaluated using Pedigree Disequilibrium Test methods. Patients: The Minnesota COME/ROM Family Study, a group of 142 families (619 subjects) with multiple affected individuals with COME/ROM. Main Outcome Measures: Genetic association of COME/ROM with polymorphisms in FBXO11.Results: The FBXO11 SNPs are contained in a single linkage disequilibrium haplotype block. Ten of the 13 SNPs were sufficiently polymorphic in the sample to permit analysis. In univariate genetic analysis, 1 reference SNP (hereinafter rs) (rs2134056) showed nominal evidence of association to COME/ROM (P=.02), and 2 SNPs approached significance (rs2020911, P = .06; rs3136367, P=.09). In multivariable analyses, including known risk factors for COME/ROM (sex, exposure to smoking, attending day care centers, no prior breastfeeding, and having allergies), the evidence of independent association was reduced for each SNP (eg, rs2134056, from P=.02 to P=.08). In subsequent analyses using the Pedigree Disequilibrium Test, the association of FBXO11 SNP rs2134056 (P=.06) with COME/ROM was confirmed. Incorporating multiple SNPs in 2-and 3-locus SNP haplotypes, those haplotypes containing rs2134056 also exhibited evidence of association of FBXO11 and COME/ ROM (P values ranging from .03 to .10). Conclusion:We have observed evidence consistent with an association between polymorphisms in FBXO11, the human homologue of the Jeff mouse model gene, and COME/ROM.

FBXO11, a regulator of the TGFβ pathway, is associated with severe otitis media in Western Australian children

“…In our study, the FBXO11 association was observed across the spectrum (rAOM/COME) of clinically severe OM. This is broadly concordant with a previously reported association between FBXO11 and recurrent OM/COME in The Minnesota COME/ROM Family Study, 10 although we did not replicate association with the same SNP (rs2134056), which falls outside the haplotype blocks containing our disease-associated SNPs. Conversely, the previous study did not observe an association with rs330787, the most significantly associated SNP observed here, despite the fact that all three cohorts comprise predominantly Caucasian children.…”

“…FBXO11/ rs330787 and FBXO11/rs12712997, which are associated in both the primary and replication cohorts, fall in LD block 1. FBXO11/rs2134056, which was associated with COME/ROM in the Minnesota Family Study 10 but was not associated in our study, does not belong to either LD block (r 2 p0.12).…”

“…No other polymorphisms in FBXO11 showed significant association with disease, including FBXO11/rs2134056, which was previously shown to be associated with OM. 10 There was no significant association with any EVI1 polymorphism.…”

“…Allelic association analysis of single-nucleotide polymorphism (SNP) variants in the human FBXO11 gene carried out in the predominantly Caucasian Minnesota COME/ROM Family Study cohort identified nominal evidence for association at rs2134056 (P ¼ 0.02) (see ref. 10).…”

A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2

“…Details of recruitment and examination of the study participants have been described previously (Daly et al 1996(Daly et al , 2004Segade et al 2006). Index cases (probands) who had tympanostomy tube surgery for COME/ROM and their family members were recruited for the study.…”