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

Santos‐Cortez, Regie Lyn P.; Hutchinson, Diane S.; Ajami, Nadim J.; Reyes-Quintos, Ma. Rina T.; Tantoco, Ma. Leah C.; Labra, Patrick John; Lagrana, Sheryl Mae; Pedro, Melquiadesa; Llanes, Erasmo Gonzalo D.V.; Gloria-Cruz, Teresa Luisa I; Chan, Abner L.; Paz, Eva Maria Cutiongco‐de la; Belmont, John W.; Chonmaitree, Tasnee; Abes, Generoso T.; Petrosino, Joseph F.; Leal, Suzanne M.; Chiong, Charlotte M.

doi:10.1186/s40249-016-0189-7

Cited by 25 publications

(19 citation statements)

References 30 publications

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“…Moreover, both missense and nonsense variants reduced A antigen expression in epithelial cells (Figure 4). However, we did not find middle ear microbiome differences due to the p.Arg202* variant, which is possibly due to the inclusion of indigenous individuals who also carry A2ML1 variants that influence the middle ear microbiome 32 (Figures 1B and 2). On the other hand, the c.461G>A (p.Trp154*) variant influences richness and complexity of the middle ear microbiome (Figure 2), which is consistent with findings in the gastrointestinal tract though predominant taxa in the gut may be different.…”

Section: Discussionmentioning

confidence: 58%

FUT2 Variants Confer Susceptibility to Familial Otitis Media

Santos‐Cortez

Chiong

Frank

et al. 2018

The American Journal of Human Genetics

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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 ¼ 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p ¼ 1.2 3 10 À5) and US trios (TDT p ¼ 0.01). The c.461G>A (p.Trp154*) variant was also overtransmitted in US trios (TDT p ¼ 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10 À7) 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 ¼ 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.

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Section: Discussionmentioning

confidence: 58%

FUT2 Variants Confer Susceptibility to Familial Otitis Media

Santos‐Cortez

Chiong

Frank

et al. 2018

The American Journal of Human Genetics

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“…In middle ears of A2ML1 variant carriers, we observed a nominally significant increase in relative abundance of Fusobacteria and Bacteroidetes, which are more commonly identified as oral cavity or oropharyngeal pathogens (Santos‐Cortez, Hutchinson et al, ; Suzuki et al, ; Yang, Zhang, Li, Yang, & Shi, ). The additional finding of gingivitis as an independent risk factor for otitis media further supports the oral cavity as a potential source of otitis media pathogens in middle ears with weaker mucosal protection due to A2ML1 defects (Santos‐Cortez et al, ; Santos‐Cortez, Hutchinson et al, ). It also suggests that prevention of gum disease may be an effective public health measure towards decreasing otitis media burden in the indigenous Filipino population.…”

Section: Discussionmentioning

confidence: 99%

“…Salivary A2M is increased during inflammatory conditions in the oral cavity, such as gingivitis and periodontal disease (Pederson et al, ). Furthermore, in a microbiome study, indigenous Filipino carriers with the A2ML1 duplication and otitis media harbor bacterial pathogens that are commonly associated with dental and oropharyngeal infections, for example, Fusobacteria and Bacteroidetes (Santos‐Cortez, Hutchinson et al, ), suggesting the possibility of A2ML1‐related pathophysiologic processes in the oral cavity.…”

Section: Introductionmentioning

confidence: 99%

A2ML1and otitis media: novel variants, differential expression, and relevant pathways

Larson¹,

Magno²,

Steritz³

et al. 2019

Human Mutation

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A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media. K E Y W O R D S A2ML1, alpha-2-macroglobulin-like-1, exome sequencing, otitis media, RNA-sequencing

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“…Authors speculated that the expected loss-of-function of A2ML1 protein could influence ME microbiota composition promoting survival and growth of specific microorganism. This findings warrant further investigations on the relationship between host genotype and microbiota in OM [85].…”

Section: Chronic Suppurative Otitis Mediamentioning

confidence: 70%

Upper Respiratory Tract Microbiome and Otitis Media Intertalk: Lessons from the Literature

Folino

Ruggiero

Capaccio

et al. 2020

JCM

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Otitis media (OM) is one of the most common diseases occurring during childhood. Microbiological investigations concerning this topic have been primarily focused on the four classical otopathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes) mainly because most of the studies have been conducted with culture-dependent methods. In recent years, the introduction of culture-independent techniques has allowed high-throughput investigation of entire bacterial communities, leading to a better comprehension of the role of resident flora in health and disease. The upper respiratory tract (URT) is a region of major interest in otitis media pathogenesis, as it could serve as a source of pathogens for the middle ear (ME). Studies conducted with culture-independent methods in the URT and ME have provided novel insights on the pathogenesis of middle ear diseases through the identification of both possible new causative agents and of potential protective bacteria, showing that imbalances in bacterial communities could influence the natural history of otitis media in children. The aim of this review is to examine available evidence in microbiome research and otitis media in the pediatric age, with a focus on its different phenotypes: acute otitis media, otitis media with effusion and chronic suppurative otitis media.

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

Cited by 25 publications

References 30 publications

FUT2 Variants Confer Susceptibility to Familial Otitis Media

FUT2 Variants Confer Susceptibility to Familial Otitis Media

A2ML1and otitis media: novel variants, differential expression, and relevant pathways

Upper Respiratory Tract Microbiome and Otitis Media Intertalk: Lessons from the Literature

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