Bivariate Analysis of Age-Related Macular Degeneration Progression Using Genetic Risk Scores
Bivariate Analysis of Age-Related Macular Degeneration Progression Using Genetic Risk Scores
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DOI：
10.1534/genetics.116.196998
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发表时间：
2017-05-01
期刊：
影响因子：
3.3
通讯作者：
Chen, Wei
中科院分区：
文献类型：
--
作者：
Ding, Ying;Liu, Yi;Chen, Wei
在发达国家，老年性黄斑变性（AMD）是导致失明的主要原因。虽然许多AMD易感性变异已被确定，但它们对AMD进展的影响尚未阐明。使用两项大型临床试验——年龄相关性眼病研究（AREDS）和AREDS2的数据，我们评估了34种已知风险变异对疾病进展的影响。在此过程中，我们计算了眼水平至晚期AMD的时间，并使用双变量生存分析方法对其建模，适当地考虑了眼间相关性。然后，我们基于这34种风险变异得出遗传风险评分（GRS），并分析其对AMD进展的影响。最后，我们使用AREDS数据拟合基于人口统计学和环境因素、眼平级AMD严重程度评分和GRS的进展预测模型，并使用AREDS2队列对模型进行测试。我们观察到，在两个队列中，GRS与AMD进展显著相关，AREDS的影响强于AREDS2 (AREDS：风险比(HR) = 1.34, p = 1.6 x 10(-22)；AREDS2: HR = 1.11, P = 2.1 × 10(-4))。在预测AMD进展方面，将GRS与人口统计学/环境危险因素结合，显著提高了预测效果。然而，当基线眼平严重程度评分作为预测因子时，包括GRS在内的任何其他风险因素仅提供了很小的额外预测能力。我们预测疾病进展风险的模型在两个队列中都表现出令人满意的效果，我们建议将其与基线AMD严重程度评分加上基线年龄、教育水平和吸烟状况一起使用，无论是否伴有GRS。
Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. While many AMD susceptibility variants have been identified, their influence on AMD progression has not been elucidated. Using data from two large clinical trials, Age-Related Eye Disease Study (AREDS) and AREDS2, we evaluated the effects of 34 known risk variants on disease progression. In doing so, we calculated the eye-level time-to-late AMD and modeled them using a bivariate survival analysis approach, appropriately accounting for between-eye correlation. We then derived a genetic risk score (GRS) based on these 34 risk variants, and analyzed its effect on AMD progression. Finally, we used the AREDS data to fit prediction models of progression based on demographic and environmental factors, eye-level AMD severity scores and the GRS and tested the models using the AREDS2 cohort. We observed that GRS was significantly associated with AMD progression in both cohorts, with a stronger effect in AREDS than in AREDS2 (AREDS: hazard ratio (HR) = 1.34, p = 1.6 x 10(-22); AREDS2: HR = 1.11, P = 2.1 x 10(-4)). For prediction of AMD progression, addition of GRS to the demographic/environmental risk factors considerably improved the prediction performance. However, when the baseline eye-level severity scores were included as the predictors, any other risk factors including the GRS only provided small additional predictive power. Our model for predicting the disease progression risk demonstrated satisfactory performance in both cohorts, and we recommend its use with baseline AMD severity scores plus baseline age, education level, and smoking status, either with or without GRS.