FUT2 Variants Confer Susceptibility to Familial Otitis Media.

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154∗) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202∗) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10-5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154∗) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10-7) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154∗, and p.Arg202∗-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.

Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene.

BACKGROUND: Previously rare A2ML1 variants were identified to confer otitis media susceptibility in an indigenous Filipino community and in otitis-prone US children. The goal of this study is to describe differences in the middle ear microbiome between carriers and non-carriers of an A2ML1 duplication variant that increases risk for chronic otitis media among indigenous Filipinos with poor health care access. METHODS: Ear swabs were obtained from 16 indigenous Filipino individuals with chronic otitis media, of whom 11 carry the A2ML1 duplication variant. Ear swabs were submitted for 16S rRNA gene sequencing. RESULTS: Genotype-based differences in microbial richness, structure, and composition were identified, but were not statistically significant. Taxonomic analysis revealed that the relative abundance of the phyla Fusobacteria and Bacteroidetes, and genus Fusobacterium were nominally increased in carriers compared to non-carriers, but were non-significant after correction for multiple testing. We also detected rare bacteria including Oligella that was reported only once in the middle ear. CONCLUSIONS: These findings suggest that A2ML1-related otitis media susceptibility may be mediated by changes in the middle ear microbiome. Knowledge of middle ear microbial profiles according to genetic background can be potentially useful for therapeutic and prophylactic interventions for otitis media and can guide public health interventions towards decreasing otitis media prevalence within the indigenous Filipino community.

Genetic and Environmental Determinants of Otitis Media in an Indigenous Filipino Population.

OBJECTIVE: To identify genetic and environmental risk factors for otitis media in an indigenous Filipino population. STUDY DESIGN: Cross-sectional study. SETTING: Indigenous Filipino community. SUBJECTS AND METHODS: Clinical history and information on breastfeeding, tobacco smoke exposure, and swimming were obtained from community members. Heads of households were interviewed for family history and personal beliefs on ear health. Height and weight were measured. Otoscopic findings were described for the presence and character of perforation or discharge. An A2ML1 duplication variant that confers otitis media susceptibility was Sanger sequenced in all DNA samples. Co-occurrence of middle ear bacteria detected by 16S rRNA gene sequencing was determined according to A2ML1 genotype and social cluster. RESULTS: The indigenous Filipino population has a ~50% prevalence of otitis media. Young age was associated with otitis media (4 age strata; P = .004); however, age was nonsignificant as a bistratal or continuous variable. There was no association between otitis media and sex, body mass index, breastfeeding, tobacco exposure, or deep swimming. In multivariate analyses, A2ML1 genotype is the strongest predictor of otitis media, with an odds ratio of 3.7 (95% confidence interval: 1.3-10.8; P = .005). When otitis media diagnoses were plotted across ages, otitis media was observed within the first year of life, and chronic otitis media persisted up to adulthood, particularly in A2ML1-variant carriers. CONCLUSION: Among indigenous Filipinos, A2ML1 genotype is the primary risk factor for otitis media and main determinant of disease progression, although age, the middle ear microbiome, and social clusters might modulate the effect of the A2ML1 genotype.

Rare A2ML1 variants confer susceptibility to otitis media.

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.

The voice test for newborn hearing screening

OBJECTIVES. The goal of the study is to find a reasonable aIternative test that can be utilized in the Philippine setting to operationalize the Universal Newborn Hearing Screening Act. Thus the components of the Voice Test were studied. The objectives of the study are to determine: (1) which of the two words "Baah" and "Psst" is better for newborn hearing screening rocedure as far as their physical characteristics are concerned, ~) how do the two words "Baah" and Psst" differ between genders and distance from sound source, (3) to determine the proportion of the participants who could recite the words at intensity of 80db or louder. METHODS. Frequency characteristics and sound intensity differences of two words "Baah" and "Psst" were determined and ompared. RESULTS. The word "Baah" exhibited more favorable physical attributes over the word 'Psst" for purposes of being a screening tool for newborn hearing assessment. CONCLUSION. This study reports the results of an initial step in the search for an inexpensive, feasible, and valid tool for neonatal earing screening. Correlation studies with speech developmental milestones may eventually enhance the usefulness of the voice test.

The ubiquitous TB otitis media: A review of diagnosis and treatment outcomes

OBJECTIVE: The purpose of this review is to improve the detection of TB otitis media cases and its treatment outcome by describing the varied clinical presentations, discussing the importance, limitations and frontiers of possible diagnostic tests and illustrating the roles of medical and surgical interventions METHOD: A review of available literature was done. The search included published researches on TB Otitis Media and related articles on tuberculosis. RESULTS: The review included aspects of the clinical presentation, diagnostic considerations, and treatment options, both medical and surgical, of tuberculous otitis media. CONCLUSION: Tuberculous otitis media presents with a variety of clinical features so that a high index of suspicion is very important. Diagnostic examinations are available but are varied depending on the clinical presentation. Definitive treatment is mainly medical with anti- Koch's medications.

Auditory brainstem response latencies of infants and maternal eposure to environmental toxic product

OBJECTIVE: To explore the effects of pesticide exposure on the auditory system, specifically on hearing status based on auditory brainstem responses. METHODS: A cohort of pregnant women was identified in several communities in a rural area from April 2002 to February 2003 and followed up until delivery. Mother-infant dyads were assessed for exposure to pesticides. Maternal and fetal exposures to environmental toxic products were determined by measuring levels in maternal hair and blood, and infant cord blood, hair, and meconium, respectively. Hearing status was measured using otoacoustic emissions (OAE) and confirmed by diagnostic auditory brainstem responses (ABR) measured at 80, 60, and 40 decibels. Waves I, III, V were identified and absolute latencies measured, including inter-peak latencies from waves 11III, I-V, and III-V. Pesticide exposure was then correlated with latencies of Waves I, III, V, and interpeak latencies of waves I-III, IIV, and III-V. Hearing loss and pesticide exposures were correlated with Griffiths Mental Development Scores (GMDS). RESULTS: Significant delays in the ABR wave latencies were noted in the group with exposure to pesticides. Propoxur was the most common toxic product detected in infants and meconium the best substrate for its detection. There was a 1.4% risk of hearing loss with exposure to propoxur (RR=0.52 (0.12-2.30), p = 0.06), a 6.25% risk with cypermethrin exposure (RR= 4.53 (0.61133.64), P = 0.10) and 6.25% risk with pretilachlor exposure (3.13 (0.44-22.30), p = 0.07). Griffith's Mental Developmental Scale scores (GMDS- hearing and speech subscale and general quotient scores) were not significantly different between exposed and unexposed groups. However, three infants with positive exposures and hearing loss had below average, or low to average scores using this scale. CONCLUSION: Maternal exposure to environmental toxic products may affect the auditory pathway in infants at birth. Pregnant women should limit their exposure to such toxic products in order to avoid neurodevelopmental effects particularly on hearing because this is very important in the critical stage of language and speech development.

Training of nurses in ear examination and hearing screening in the school setting.

The objectives of this study were to determine the agreement between the ear examination findings of the otorhinolaryngologist (trainer) and the elementary school nurse (trainee) after training with the use of a penlight and to determine the mean sound pressure level (SPL) produced by school nurses as a standard parameter for hearing screening using a 512 tuning fork after training on tuning fork testing by the otorhinolaryngologist. Training workshops in ear examination using a penlight and hearing screening using a 512 tuning fork were conducted for school nurses. Data for assessment of ear examination skills and production of SPL were collected by questionnaire and observation of performance. Kappa statistics were used to assess agreement between trainees' and trainer's responses. Mean and standard deviation were determined for the assessment of the SPL produced. Results showed an excellent agreement between the school nurses' and otorhinolaryngologist's observations on ear examination. These included observations of the ear canal, visualization of the tympanic membrane and identification of unusual findings such as wax and discharge. The majority of nurses responded positively in terms of the ease and confidence in performance of the procedure. Regarding tuning fork testing, the nurses were able to produce significant SPL. The mean SPL produced by the nurses using a 512 tuning fork was 56.316 dB.