Genetic Epidemiology of Otitis Media

描述（由申请人提供）：中耳炎（OM）是一个世界性的儿科保健问题。在美国的医生办公室实践中，这是在15岁以下儿童中最常见的诊断。使用双胞胎研究方法，我们最近证明了中耳积液（MEE）的时间，MEE的发作次数和急性中耳炎（AOM）的发作次数具有很强的遗传成分。MEE对时间遗传力的点估计为0.73。虽然有重要证据表明，对复发性/持续性OM的易感性在很大程度上是由遗传决定的，但导致易感性的具体基因尚不清楚。我们确定OM基因的总体研究策略是采用三阶段研究设计，这将使我们能够平衡成本效率和检测OM基因的统计能力。将招募500对有鼓室造瘘管插入史（受影响）的兄弟姐妹，他们的父母和可用的未受影响的全兄弟姐妹。将从每个受试者中获取血液样本进行基因分型。第一阶段将对受影响的兄弟姐妹及其父母进行10cm基因组扫描。在这一阶段，我们将使用一个相对宽松的显著性标准，相当于LOD约为1.0，以确定进一步研究的染色体区域，这将包括在第一阶段的阳性区域进行高密度扫描（约1厘米）。对于这种高密度扫描，将采用严格的显著性标准。最后，我们将使用基于家族的关联/连锁不平衡分析（TDT），对位置候选基因中的单核苷酸多态性进行分析，以确定影响OM易感性的特定基因。本研究旨在确定在复发性/持续性OM的发展中起作用的基因。这可能使我们更好地了解OM的病理生理，从而制定更好的预防和治疗方法。

DESCRIPTION (provided by applicant): Otitis media (OM) is a worldwide pediatric health care problem. In physician office practices in the United States, it is the most common diagnosis made in children under 15 years of age. Using the twin study approach, we have recently demonstrated that time with middle ear effusion (MEE), number of episodes of MEE and number of episodes of acute otitis media (AOM) have a strong genetic component. The point estimate of heritability of time with MEE was 0.73. While there is significant evidence that susceptibility to recurrent/persistent OM is largely genetically determined, the specific genes which confer susceptibility are unknown. Our overall research strategy to identify genes underlying OM is to apply a three-stage study design that will allow us to balance cost efficiency with statistical power to detect OM genes. Five hundred pairs of siblings with a history of tympanostomy tube insertion (affected), their parent(s) and available non-affected full siblings will be recruited. A blood sample will be obtained from each subject for genotyping. The first stage will be to perform a 10 cM genome-scan in affected pairs of siblings and their parent(s). At this stage we will use a relatively generous significance criterion equivalent to a LOD of about 1.0 to identify chromosomal regions for further studies which will consist of a high density scan (approximately 1 cM) in the positive regions from the first stage. For this high-density scan a stringent significance criterion will be applied. Finally, we will use family based association/linkage disequilibrium analysis (TDT) of single nucleotide polymorphisms within positional candidate genes to identify specific genes that influence susceptibility to OM.The present study proposes to identify the genes that play a part in the development of recurrent/persistent OM. This may enable us to better understand the pathophysiology of OM and thus develop better methods for its prevention and treatment.