Genetic Susceptibility to Papilloma-induced Voice Disturbance

描述（由申请人提供）：数百万美国人感染一种或多种类型的人乳头瘤病毒（HPV）。100多种HPV类型中的许多是生殖器的嗜性，并分为两大类：引起宫颈瘤形成的HPV类型;和引起尖锐湿疣（生殖器疣）的HPV类型。在儿童中，不幸从母亲那里获得了湿疣病毒类型，感染产生了最常见的喉良性肿瘤，复发性呼吸道乳头状瘤病（RRP）。RRP导致语音障碍，这与非常显著的发病率相关，并降低生活质量。人类的声音是我们物种最独特和最具决定性的方面之一，因为它直接导致我们参与复杂通信的能力。慢性声音障碍提示耳鼻喉科医生进行评估，不受控制的疾病可能会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。大多数患者必须接受多次手术。这种疾病可能会进入缓解一些，但声音嘶哑往往持续终身。我们指出RRP具有遗传易感性，在本申请中，我们建议使用RRP作为模型来确定宿主对HPV易感性的遗传基础，从而实现合理的治疗开发。RRP工作组、19家医疗机构、基因组科学中心和两个患者支持团体之间的持续合作产生了有史以来最广泛的RRP DNA库。该储存库将扩大到进行全基因组遗传关联研究所需的规模，这些研究足以识别易感基因。通过比较患者与其父母以及对照，然后进行传递不平衡检验和病例-对照遗传关联分析，确定易感基因座。还将进行数量性状基因座分析，其中将基因型与疾病侵袭性进行比较。为了减少费用，将使用经验证的两步法。仅对三分之一的样品进行300，000个SNP/受试者的完整基因分型，然后仅在步骤1中鉴定的最有希望的基因座处对其余样品进行基因分型。此外，将对已知在HPV细胞生物学中发挥作用的约20个候选基因进行高密度遗传关联研究。最后，将对先验和后验研究确定的所有候选基因进行测序，以确定导致这种改变生命的疾病的遗传病变。

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.