Prospective Huntington At Risk Observational Study (PHAROS)

描述(由申请人提供)：PHAROS(前瞻性亨廷顿风险观察研究)是一项多点纵向项目，旨在了解：(1)亨廷顿病(HD)早期显性疾病的基因特异性临床先兆和预测因子，以及它们与环境和遗传修饰因素的关系，以及(2)研究选择不通过预测性DNA测试了解其基因携带者状况的HD高危人群的可行性、心理社会和伦理考虑。1999年7月至2004年1月，1001名有HD直接风险(50：50)的成年人同意参加PHAROS，条件是：(1)对他们的血液样本进行突变HD基因分析，扩大的CAG三核苷酸重复，以及(2)CAG分析的个别结果永远不向任何人披露，甚至不向研究参与者披露。到目前为止，这个临床上未受影响的基线队列平均被跟踪了4年，以确定疾病是否以及何时变得明显，这是通过出现明确的运动特征来衡量的 HD(表观转化)，并由不知道基因状态的评分员判断。我们建议将对Pharos队列的评估延长至2009年，以积累足够的表观转化事件，以满足我们最初的研究目标并定义表观转化曲线的形状。扩大对Pharos队列研究的需要提供了检查DNA和RNA损伤的标记物的机会，分别是8-羟基-2‘脱氧鸟苷(8-OH2’dG)和8-羟基鸟苷(SOHrG)， 它们在患有显性HD的个体和一些尚未表现出HD的基因携带者的血液中升高。对研究参与者同意的血液和尿液样本进行分析将有所帮助 确定：(1)8-OH2‘DG和SOHrG是否在HD基因携带者中特异性升高，(2)升高到什么程度 海拔高度标志着HD的临床出现，以及(3)DNA/RNA这些指标的潜在价值 损伤作为HD状态和致病活动的生物标志物。总体而言，扩大和完成对法罗队列的纵向评估以及DNA和RNA损伤标志物的检查将：(1)澄清HD早期临床发作的比率和特征，(2)对有HD风险的成年人进行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损伤测量作为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进行能够推迟携带导致HD的致命基因的个体的发病。这些知识还将告知患有致残性遗传病的高危人群如何应对有关其未来健康的挥之不去的不确定性以及关于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.