Abstract
Over the last decade, genetic studies, including genome-wide association studies (GWAS), have accelerated the discovery of genes and genomic regions contributing to primary open-angle glaucoma (POAG), a leading cause of irreversible vision loss. Here, we review the findings of genetic studies of POAG published in English prior to September 2019. In total, 74 genomic regions have been associated at a genome-wide level of significance with POAG susceptibility. Recent POAG GWAS provide not only insight into global and ethnic-specific genetic risk factors for POAG susceptibility across populations of diverse ancestry, but also important functional insights underlying biological mechanisms of glaucoma pathogenesis. In this review, we also summarize the genetic overlap between POAG, glaucoma endophenotypes, such as intraocular pressure and vertical cup–disc ratio (VCDR), and other eye disorders. We also discuss approaches recently developed to increase power for POAG locus discovery and to predict POAG risk. Finally, we discuss the recent development of POAG gene-based therapies and future strategies to treat glaucoma effectively. Understanding the genetic architecture of POAG is essential for an earlier diagnosis of this common eye disorder, predictive testing of at-risk patients, and design of gene-based targeted medical therapies none of which are currently available.
摘要
原发性开角型青光眼(POAG)是导致不可逆视力丧失的主要原因, 在过去十年中, 遗传学研究的新发现, 包括全基因组关联研究, 加速了POAG基因和基因组区域的新发现。我们回顾了2019年9月之前英文发表的关于POAG遗传研究的研究成果。在全基因组水平, 共有74个基因组区域与POAG的易感性相关。近期关于POAG的 GWAS研究不仅提供了全球以及不同种族的POAG基因易感性的遗传危险因素, 还提供了这些易感基因在青光眼病理发病机制中的重要作用。在这篇综述中, 我们总结了POAG易感基因之间的相互作用, 青光眼内在表型 (如眼内压和垂直杯盘比) 以及其与他眼病之间的遗传的相关性。我们还讨论了最近研发的增加POAG基因座发现能力及预测POAG风险的方法。最后, 我们讨论了基于POAG基因治疗的最新进展以及有效治疗青光眼的未来策略。了解POAG的遗传信息对于早期诊断这种常见的眼部疾病, 对高危患者进行早期预测以及设计目前尚无可用的基于基因的靶向药物治疗至关重要。
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Acknowledgements
HC is supported by a National Eye Institute (NEI) grant R01 EY027004 and a National Institute of Diabetes and Digestive and Kidney Diseases grant R01 DK116738. JLW is supported by the two following NIH/NEI grants: R01 EY022305 and P30 EY014104. APK is supported by a Moorfields Eye Charity Career Development Fellowship.
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Choquet, H., Wiggs, J.L. & Khawaja, A.P. Clinical implications of recent advances in primary open-angle glaucoma genetics. Eye 34, 29–39 (2020). https://doi.org/10.1038/s41433-019-0632-7
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