Prospective Huntington At Risk Observational Study (PHAROS)

描述（申请人提供）：PHAROS（前瞻性亨廷顿风险观察性研究）是一个多中心纵向项目，旨在获得以下方面的知识：（1）亨廷顿病（HD）基因特异性临床前兆和早期显性疾病的预测因子及其与环境和遗传修饰剂的关系，和（2）可行性，在研究HD高风险成人人群中的心理社会和伦理考虑，这些成人选择不通过预测性DNA检测了解其基因携带者状态。在1999年7月至2004年1月期间，1001名有HD直接风险（50：50）的成年人同意在以下条件下参加PHAROS：（1）分析他们的血液样本中的突变HD基因，一种扩展的CAG三核苷酸重复序列，（2）CAG分析的个人结果永远不会向任何人透露，甚至不会向研究参与者透露。到目前为止，对基线时临床上未受影响的队列进行了平均4年的随访，以确定疾病是否以及何时变得明显，如通过以下明确运动特征的出现所测量的： HD（“表型转化”）和由不了解基因状态的评定者判断。 我们建议将PHAROS队列的评估延长至2009年，以积累足够的表型转化事件来实现我们最初的研究目标并定义表型转化曲线的形状。扩展PHAROS队列研究的需要提供了分别检查DNA和RNA损伤标记物8-羟基-2 '脱氧鸟苷（8-OH 2'dG）和8-羟基鸟苷（SOHrG）的机会， 其在患有明显HD的个体和一些尚未表现HD的基因携带者的血液中升高。对同意的研究参与者的血液和尿液样本进行分析将有所帮助 确定：（1）HD基因携带者是否特异性升高8-OH 2 'dG和SOHrG，（2）升高到何种程度 升高标志着HD的临床出现，（3）这些DNA/RNA指数的潜在价值 损伤作为HD状态和致病活性的生物标志物。总的来说，扩展和完成PHAROS队列的纵向评估以及DNA和RNA损伤标志物的检查将：（1）阐明HD早期临床发作的发生率和特征，（2）在HD风险成人长期研究中的安全性、可行性、心理社会和伦理考虑，以及（3）DNA/RNA损伤指标作为HD生物标志物的实用性。这项研究的知识将使临床试验的有效设计和适当的进行，以延迟携带导致HD的致命基因的个体的疾病发作。这些知识还将告知有患致残性遗传疾病高风险的人如何应对其未来健康的挥之不去的不确定性以及他们参与研究的复杂选择。

DESCRIPTION (provided by applicant): PHAROS (Prospective Huntington At Risk Observational Study) is a multi-site longitudinal project that aims to gain knowledge about: (1) Huntington's disease (HD) gene-specific clinical precursors and predictors of early manifest disease and their relationship to environmental and genetic modifiers, and (2) the feasibility, psychosocial and ethical considerations in studying a population of adults at high risk for HD who have chosen not to learn of their gene carrier status by predictive DNA testing. Between July 1999 and January 2004, 1001 adults at immediate risk (50:50) for HD consented to participate in PHAROS under conditions that: (1) their blood sample be analyzed for the mutant HD gene, an expanded CAG trinucleotide repeat, and (2) individual results of the CAG analysis never be disclosed to anyone, not even to the research participant. This clinically unaffected cohort at baseline has so far been followed for an average of 4 years to determine if and when disease becomes manifest, as measured by the emergence of the unequivocal motor features of HD ('phenoconversion') and as judged by raters unaware of gene status. We propose extending assessment of the PHAROS cohort through 2009 to accrue sufficient phenoconversion events to address our original research aims and define the shape of the phenoconversion curve. The need to extend study of the PHAROS cohort provides the opportunity to examine markers of DNA and RNA damage, 8-hydroxy-2' deoxyguanosine (8-OH2'dG) and 8-hydroxyguanosine (SOHrG) respectively, which are elevated in the blood of individuals with manifest HD and in some gene carriers who have not yet manifested HD. Analysis of blood and urine samples from consenting research participants will help determine: (1) if 8-OH2'dG and SOHrG are elevated specifically in HD gene carriers, (2) to what extent elevations mark the clinical emergence of HD, and (3) the potential value of these indices of DNA/RNA damage as biomarkers of the state and pathogenic activity of HD. Collectively, extending and completing the longitudinal assessment of the PHAROS cohort and examination of DNA and RNA injury markers will: (1) clarify the rate and characteristics of the early clinical onset of HD, (2) the safety, feasibility, psychosocial and ethical considerations in long-term studies of adults at risk for HD, and (3) the utility of measures of DNA/RNA damage as biomarkers of HD. The knowledge from this research will enable the efficient design and appropriate conduct of clinical trials to delay the onset of illness in individuals who carry the lethal gene causing HD. The knowledge will also inform how persons at high risk to develop a disabling genetic disease deal with lingering uncertainties about their future health and complex choices about their participation in research.