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

基本信息

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
项目类别：
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

项目摘要

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) 或中耳感染在美国仍然是一个重要的公共卫生问题，是美国儿童临床咨询和使用抗生素的首要原因，每年造成的费用超过 50 亿美元。在世界范围内，中耳炎的发病率和患病率很高。在撒哈拉以南非洲和亚洲以及土著居民等边缘化社区，存在强有力的证据表明 OM 存在遗传易感性，但之前没有报道过罕见的 OM 易感性变异。本研究旨在： (1) 识别罕见的 OM。家族内和先证者的易感性变异；(2) 识别由于 OM 易感性变异导致的中耳微生物组差异。在本研究中，OM 被视为一种疾病谱，因此所有患有急性、慢性、渗出性或已治愈 OM 的个体都被考虑在内。该策略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 OM 易感性变异的显着关联的能力，包括：(1) 大量菲律宾土著人。 OM 患病率高的家系以及 OM 易感性变异的家族内位点异质性的证据；(2) 从出生起就对 143 个患有慢性中耳炎的家庭进行随访的病例对照队列；或复发性 OM；以及 (4) 至少 600 名先证者将接受慢性或复发性 OM 手术对于菲律宾土著人群和来自菲律宾的手术患者，微生物基因图谱也将进行，并且与 OM 易感性变异鉴定研究重叠将允许基于变异携带进行微生物概况研究，尽管每个队列在遗传上是不同的，但它们也混合在一起，从而允许在队列中复制罕见变异。在连锁分析方面，将使用DNA和微生物测序，将应用稀有变异和微生物分析的新技术，包括使用OM trios和内部管道对NGS数据进行稀有变异传输不平衡测试使用 NGS 数据和微生物基因分析来鉴定罕见变异，随后将进行蛋白质产物的小鼠中耳定位并创建突变体构建体以进行功能分析。对于新招募的三人组和家庭进行微生物组研究，中耳样本将包括分泌物和粘膜拭子，以及粘膜组织和胆脂瘤微生物多样性和相关性。将根据 OM 慢性性和 OM 易感性变异的携带来研究 OM 丰度，识别赋予 OM 易感性并导致耳朵中部微生物组变化的罕见变异可以阐明与 OM 病理生理学有关的途径，从而可以作为 OM 预防的目标。和治疗，例如，通过新药开发、抗生素选择和以基因型和/或微生物谱为指导的疫苗优先顺序。