Otitis Media Susceptibility and Middle Ear Microbial Shifts due to Gene Variants

基因变异导致中耳炎易感性和中耳微生物变化

• 批准号: 9222003
• 负责人: Regie Lyn Pastor Santos-Cortez
• 金额: $ 33.67万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-10 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222003
• 关键词: Acute; Affect; Africa; Africa South of the Sahara; Alleles; Antibiotics; Asia; Bacteroides; Bioinformatics; Birth; Cells; Child; Cholesteatoma; Chromosomes; Chronic; Clinical; Collaborations; Communities; Consult; DNA; Data; Databases; Development; Dideoxy Chain Termination DNA Sequencing; Disease; Epithelial; Epithelium; European; Family; Filipino; Functional disorder; Fusobacterium; Gene Frequency; General Hospitals; Genes; Genetic Predisposition to Disease; Genetic study; Genomics; Genotype; Haemophilus influenzae; Haplotypes; Hemophilus; Heterogeneity; Hispanic Americans; Incidence; Indigenous; Individual; Labyrinth; Latino; Liquid substance; Lod Score; Maps; Medical; Metagenomics; Methods; Microbial Biofilms; Minnesota; Minor; Morbidity - disease rate; Mucous Membrane; Mus; Native-Born; Operative Surgical Procedures; Otitis; Otitis Media; Pathway interactions; Patients; Philippines; Population; Porphyromonas; Predisposition; Prevalence; Prevention; Prevention strategy; Proteins; Pseudomonas; Public Health; Recruitment Activity; Recurrence; Reporting; Research; Ribosomal RNA; Role; Sampling; Susceptibility Gene; Swab; Techniques; Technology; Testing; Texas; Universities; Use of New Techniques; Vaccination; Vaccines; Variant; Washington; base; burden of illness; case control; cohort; cost; drug development; ear infection; effusion; exome; exome sequencing; follow-up; genetic linkage analysis; genetic pedigree; genetic variant; genome-wide; genomic profiles; healing; hearing impairment; indigenous community; influenza virus vaccine; member; microbial; microbiome; middle ear; mutant; novel; novel therapeutics; proband; public health relevance; rare variant; screening; spatiotemporal; success; transmission process; treatment strategy

 DESCRIPTION (provided by applicant) Otitis media (OM) or middle ear infection remains an important public health problem in the US. OM is the top reason for clinical consult and antibiotic use in US children, with annual cost >$5 billion. Worldwide, incidence and prevalence of OM are high in sub-Saharan Africa and Asia, and in marginalized communities such as indigenous populations. Strong evidence exists for genetic susceptibility to OM, but no rare OM susceptibility variants were previously reported. This study 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. In this study OM is treated as a disease spectrum such that all individuals with acute, chronic, effusive or healed OM are considered affected. This strategy has allowed initial success in variant and microbial profile identification and will increase power to detect significant associations. Cohorts to be studied for OM susceptibility variants include: (1) a large indigenous Filipino pedigree with high OM prevalence and evidence for intra-familial locus heterogeneity for OM susceptibility variants; (2) a case-control cohort of otitis- prone and non-otitis-prone childre who were followed from birth; (3) 143 families with chronic or recurrent OM; and (4) at least 600 trios that have a proband who will undergo surgery for chronic or recurrent OM. For the indigenous Filipino population and surgical patients from the Philippines, microbial gene profiling will be performed as well, and overlap with OM susceptibility variant identification studies will allow study of microbial profiles based on variant carriage. Even though each cohort is genetically distinct they are also admixed, thus allowing for replication of rare variants across cohorts. Although standard methods on linkage analysis, DNA and microbial sequencing will be used, new techniques in rare variant and microbial analysis will be applied, including the rare variant-transmission disequilibrium test for NGS data using OM trios and in-house pipelines for rare variant identification using NGS data and microbial gene profiling. Novel OM susceptibility genes will be followed up by mouse middle ear localization of protein products and creation of mutant constructs for functional analysis. Additionally screening for novel variants within previously identified OM susceptibility genes will be performed for newly recruited trios and families. For microbiome studies, middle ear samples will include swabs on discharge and mucosa, as well as mucosal tissue and cholesteatoma. Microbial diversity and relative abundance will be studied based on OM chronicity and carriage of OM susceptibility variants. Identification of rare variants that confer OM susceptibility and cause changes in the middle ear microbiome can illuminate pathways that are involved in OM pathophysiology, which in turn can be targeted for OM prevention and treatment, for example, by new drug development, antibiotic selection and vaccine prioritization guided by genotype and/or microbial profile.

 描述（由申请人提供） 中耳炎（OM）或中耳感染仍然是美国重要的公共卫生问题。OM是美国儿童临床咨询和抗生素使用的首要原因，每年花费超过50亿美元。在世界范围内，OM的发病率和患病率在撒哈拉以南非洲和亚洲以及土著人口等边缘化社区较高。有强有力的证据表明OM的遗传易感性，但以前没有报道过罕见的OM易感性变体。本研究旨在：（1）确定家族内和先证者中罕见的OM易感性变体;（2）确定由于OM易感性变体导致的中耳微生物组的差异。在这项研究中，OM被视为一种疾病谱，因此所有患有急性、慢性、渗出性或治愈性OM的个体都被视为受影响。这种策略已经在变异和微生物谱鉴定方面取得了初步成功，并将提高检测显著相关性的能力。研究OM易感性变异的队列包括：（1）一个具有高OM患病率和OM易感性变异家族内基因座异质性证据的菲律宾土著大家系;（2）一个从出生起就随访的易患耳炎和非易患耳炎儿童的病例对照队列;（3）143个慢性或复发性OM家庭;和（4）至少600例有先证者将因慢性或复发性OM接受手术的三人组。对于菲律宾土著人口和来自菲律宾的手术患者， 与OM敏感性变体鉴定研究重叠，将允许基于变体携带研究微生物谱。即使每个队列在遗传上是不同的，它们也是混合的，从而允许在队列中复制罕见的变异。虽然将使用连锁分析、DNA和微生物测序的标准方法，但将应用罕见变异和微生物分析的新技术，包括使用OM trios对NGS数据进行罕见变异传播不平衡测试，以及使用NGS数据和微生物基因分析进行罕见变异鉴定的内部管道。新的OM易感基因将通过小鼠中耳定位蛋白质产物和创建用于功能分析的突变体构建体来跟踪。此外，还将对新招募的三人组和家族进行先前确定的OM易感基因内的新变体筛选。对于微生物组研究，中耳样本将包括分泌物和粘膜上的拭子，以及粘膜组织和中耳瘤。将根据OM慢性和OM敏感性变体的携带情况研究微生物多样性和相对丰度。鉴定赋予OM易感性并导致中耳微生物组变化的罕见变体可以阐明参与OM病理生理学的途径，这反过来可以靶向OM预防和治疗，例如，通过基因型和/或微生物谱指导的新药开发，抗生素选择和疫苗优先级。