Genetic Susceptibility to Papilloma-induced Voice Disturbance

描述（由申请人提供）：数百万美国人感染了一种或多种人乳头瘤病毒（HPV）。在超过100种HPV类型中，许多类型对生殖器官有影响，可分为两大类：引起宫颈肿瘤的；和那些引起尖锐湿疣（生殖器疣）。对于不幸从母亲那里获得尖锐湿疣病毒类型的儿童，感染会产生最常见的喉部良性肿瘤，复发性呼吸道乳头状瘤病（RRP）。RRP引起声音障碍，这与非常显著的发病率和降低生活质量有关。人类的声音是我们这个物种最独特和最具决定性的方面之一，因为它直接导致了我们参与复杂交流的能力。慢性声音障碍需要耳鼻喉科医生进行评估，不受控制的疾病可能通过气道阻塞导致死亡。尽管外科医生能够诊断和治疗乳头状瘤，但由于没有已知的治疗方法，病变反复复发。大多数病人必须忍受多次手术。这种疾病在某些情况下可能会缓解，但声音嘶哑往往会持续一生。我们认为存在对RRP的遗传易感性，在本应用中，我们建议以RRP为模型确定宿主对HPV易感性的遗传基础，从而使合理的治疗开发成为可能。RRP工作组、19家医疗机构、基因组科学中心和两个患者支持小组之间的持续合作已经产生了迄今为止最广泛的RRP DNA库。储存库将增长到所需的大小，以进行全基因组遗传关联研究，有足够的能力来确定易感基因。将通过将患者与其父母以及对照组进行比较，然后进行传播不平衡测试和病例-对照遗传关联分析，确定易感位点。此外，将进行数量性状位点分析，其中基因型将与疾病侵袭性进行比较。为了减少费用，将采用经过验证的两步方法。30万个snp /受试者的完整基因分型仅在三分之一的样本上进行，其余样本仅在步骤1中确定的最有希望的位点上进行基因分型。此外，将对大约20个已知在HPV细胞生物学中起作用的候选基因进行高密度遗传关联研究。最后，通过先验和事后研究确定的所有候选基因将被测序，以确定导致这种改变生活的疾病的遗传病变。

DESCRIPTION (provided by applicant): Millions of Americans are infected with one or more types of human papillomavirus (HPV). Many of the more than 100 HPV types are tropic for the genital organs and fall into two general classes: those causing cervical neoplasia; and those causing condylomata (genital warts). In children, unfortunate enough to acquire the condylomatous viral types from their mothers, the infection produces the commonest benign neoplasm of the larynx, recurrent respiratory papillomatosis (RRP). RRP causes voice disturbance which is associated with very significant morbidity and degrades quality of life. Human voice is one of the most unique and defining aspects of our species as it leads directly to our ability to engage in complex communications. Chronic voice disturbance prompts evaluation by an otolaryngologist, and uncontrolled disease may lead to death through airway occlusion. Despite the surgeon being able to diagnose and manage the papillomas, the lesions recur repeatedly since there is no known cure. Most patients must endure multiple surgeries. The disease may go into remission in some but hoarseness often persists for life. We state that there is a genetic susceptibility to RRP, and in this application we propose to determine the genetic basis for host susceptibility to HPV using RRP as a model, enabling rational therapy development. Ongoing collaborations between the RRP Task Force, 19 medical institutions, the Center for Genomic Sciences and two patient-support groups has yielded the broadest-based RRP DNA repository ever assembled. The repository will be grown to the size needed for the performance of genome-wide genetic association studies that are sufficiently powered to identify susceptibility genes. Susceptibility loci will be identified by comparing the patients to their parents as well as to controls and then performing Transmission Disequilibrium Testing and case-control genetic association analyses. Also a quantitative trait locus analysis will be performed in which genotype will be compared to the disease aggressiveness. To reduce expenses, a validated two step approach will be used. Complete genotyping of 300,000 SNPs/subject is only performed on a third of the sample and the balance of the samples are then genotyped only at the most promising loci identified from step 1. Further, high density genetic association studies will be performed for ~20 candidate genes that are known to play a role in HPV cell biology. Finally, all candidate genes identified by both a priori and a postori studies will be sequenced to identify those genetic lesions responsible for this life-changing disease.