NIDCD Otitis Media Genetic Susceptibility and Middle Ear Microbial Shifts

The study funded by R01 DC015004 aims to: (1) Identify rare OM susceptibility variants within families and in probands; and (2) Identify differences in the middle ear microbiome due to OM susceptibility variants. This study will also elucidate mechanisms responsible for the formation and growth of cholesteatoma, and bony erosion and complications due to cholesteatoma e.g. intracranial, hearing/vestibular loss, facial nerve palsy. A better understanding of cholesteatoma pathogenesis will potentially reveal novel drug targets, which can lead to new non-surgical therapies for cholesteatomatous OM. Our specific aims for this administrative supplement are: Aim 1 -- Perform RNA-sequencing using cholesteatoma samples collected from Filipino and Colorado patients who will be screened for FUT2, SPINK5 and A2ML1 variants; and Aim 2 -- Using network analysis, identify bone-expressed proteins potentially interacting with FUT2, SPINK5 or A2ML1, then test protein expression in archival human temporal bone in direct contact with cholesteatoma.]]>
Inclusion Criteria: Any patient older than 6 months and younger than 90 years of age who will undergo or has previously undergone ear surgery (e.g. ventilation tube insertion, tympanoplasty, mastoidectomy) for any type of OM (acute, recurrent, chronic, effusive, mucinous, etc.), and both of the participant's biological parents. The age range includes parents as participants, who are expected to be adult. We also expect to recruit adult patients, who may or may not have parents available for study enrollment. In our previous study (Santos-Cortez et al. 2015, 2016) we identified otitis media patients who are less than 1 year old and >80 years old, thus our age range for study recruitment includes these ages. Ideally, we want both biological parents to provide a saliva sample so we can obtain DNA samples from a full trio. However, if DNA samples from both parents are not available, we will still enroll the participant if he/she is willing to provide all samples available for collection, including an RNA sample and/or microbial samples, from the middle ear and nasopharynx. This will allow us to include the participant's samples in studies on differences in the microbiome and RNA expression due to genetic variants. DNA saliva samples may also be collected from siblings or other biological family members that are willing to participate in the study. Salivary DNA from parents, siblings, or other biological family members may be collected before or after the participant's surgery. Any patient with Down syndrome. Patients with Down syndrome have a high predisposition to OM. The patient's chart will be checked for a physician's note determining if they have Down Syndrome. Exclusion Criteria: Patients with known craniofacial anomaly (e.g. cleft palate), immunodeficiency, ciliary defect, or syndrome (i.e. other than Down syndrome) that increases predisposition to OM. Patients wherein OM is a secondary infection due to a history of [a] trauma to the eardrum, temporal bone region or middle ear (e.g. barotrauma), or [b] problems in the outer ear canal (e.g. severe external ear infection). Children less than 6 months old. Adult participants greater than 90 years old. ]]>
Our group was the first to identify rare variants in a novel gene A2ML1 as being involved in predisposition to nonsyndromic otitis media in humans. An A2ML1 duplication variant was shown to confer a strong risk for developing early-onset otitis media in indigenous Filipino individuals with chronic otitis media and otitis-prone children from Texas, and induce changes in the middle ear microbiome. Since this discovery, we identified additional variants for otitis media susceptibility in multiple cohorts from Manila, Texas, Minnesota, Colorado and Helsinki. This work demonstrated that (1) a common complex disease can be partly due to common or rare coding variants based on family-based and case-control studies, (2) intra-familial genetic heterogeneity is common in otitis media families, and (3) multiple variants contribute to otitis media phenotype per individual. Our findings are further supported by RNA-sequence and 16S rRNA/microbiome data. Within the Colorado cohort, we identified candidate genes for cholesteatoma using additional exome sequencing data.]]>