A Phase 2 Study of the Value of Pre-symptomatic Genetic Risk Assessment for Age-Related Macular Degeneration

项目摘要/摘要 在过去的二十年里，我们了解到CFH、ARMS2/HTRA1和其他遗传基因座的变异是 老年性黄斑变性(AMD)的主要危险因素和营养补充 AREDS2抗氧化维生素、矿物质和类胡萝卜素可以减缓这种失明疾病的进展。 尽管美国眼科学会(AAO)建议反对常规的基因检测 对于AMD风险，许多公众都表示有兴趣进行这种检测，并直接面向消费者 实验室已经将其商业化销售。AAO的专家小组并没有断言这些测试不会 准确反映AMD最终导致视力丧失的风险，但没有证据表明 AMD风险对行为有任何可量化的影响，可以减少老年人AMD的发生率 好几年了。一项前瞻性研究表明，了解AMD风险可以降低AMD几十年的发病率 后来将解决这一争议，并将与AAO专家的研究建议一致 专家小组，但由于科目众多，所需时间较长，目前尚不可行。相反， 我们建议进行一项更短的2期随机临床试验，以研究健康行为的可量化生物标志物 (皮肤和眼睛类胡萝卜素水平)对AMD风险的了解有所改善。我们假设 被告知最终患上AMD的高风险的人将更有可能在 与晚年AMD发病率下降相关的行为，如戒烟，减肥， 与推迟检测的受试者相比，减少光照暴露，以及饮食中富含胡萝卜素 被告知风险较低。这些生活方式的改变将导致叶黄素、玉米黄质和 用共振拉曼光谱(RRS)和反射率测量皮肤一年内的其他类胡萝卜素 光谱(RS)、自发荧光成像(AFI)和荧光寿命成像眼底镜 (Flio)在眼睛里。我们将进行一项即刻与延期的随机对照临床试验。 以3：1的比例披露了多达80名18岁的正常人患老年性黄斑变性的风险。全身的和眼睛的 类胡萝卜素状态将通过皮肤RRS和RS以及眼睛AFI和Flio客观地评估。我们预计 被告知AMD高风险的受试者将更有可能发起并维持积极的生活方式改变 在为期一年的研究访问中，这将显著提高他们的皮肤和眼睛类胡萝卜素得分。我们还将 确定AMD遗传风险与基线眼部和全身类胡萝卜素状态的相关性 目前和较新的成像方法。

Project Summary/Abstract In the past two decades, we have learned that variants in CFH, ARMS2/HTRA1 and other genetic loci are major risk factors for age-related macular degeneration (AMD) and that nutritional supplementation with AREDS2 antioxidant vitamins, minerals, and carotenoids could slow the progression of this blinding disorder. Despite recommendations by the American Academy Ophthalmology (AAO) against routine genetic testing for AMD risk, many members of the public express an interest in pursuing such testing, and direct-to-consumer laboratories already market them commercially. The AAO's expert panel did not assert that these tests do not accurately reflect eventual risk of visual loss from AMD, but rather that there is no proof that knowledge of AMD risk has any quantifiable impact on behavior that could mitigate the incidence of AMD in their senior years. A prospective study to show that knowledge of AMD risk could decrease incidence of AMD decades later would settle this controversy and would be consistent with research recommendations of the AAO expert panel, but it is not currently feasible due to the large number of subjects and prolonged time required. Instead, we propose a shorter, Phase 2 randomized clinical trial to study if quantifiable biomarkers of healthy behavior (skin and ocular carotenoid levels) improve in response to knowledge of AMD risk. We hypothesize that individuals who are informed of a high risk of eventual AMD will be more likely to make sustained changes in behavior associated with decreased incidence of AMD later in life such as smoking cessation, weight loss, decreased light exposure, and diets rich in carotenoids relative to subjects who have deferred testing or who are informed of low risk. These lifestyle changes will then result in improved levels of lutein, zeaxanthin, and other carotenoids measured in the skin at one year by resonance Raman spectroscopy (RRS) and reflectance spectroscopy (RS) and by autofluorescence imaging (AFI) and fluorescence lifetime imaging ophthalmoscopy (FLIO) in the eye. We will conduct a randomized, controlled clinical trial of immediate versus deferred disclosure of AMD risk in a 3:1 ratio in up to 80 normal individuals age 18 to 64. Systemic and ocular carotenoid status will be assessed objectively by skin RRS and RS and by ocular AFI and FLIO. We expect that subjects informed of high risk of AMD will be more likely to initiate and sustain positive lifestyle changes that will raise their skin and ocular carotenoid scores significantly at their one-year study visit. We will also determine correlations between AMD genetic risk with baseline ocular and systemic carotenoid status using current and newer methods of imaging.