Associations Between Structural Phenotype and Polygenic Risk Scores in Intermediate Age-Related Macular Degeneration - A MACUSTAR Report.

IF 2.6 3区医学 Q2 OPHTHALMOLOGY

Translational Vision Science & Technology Pub Date : 2025-09-02 DOI:10.1167/tvst.14.9.37

Lukas Schloesser, Jan H Terheyden, Charlotte Behning, Hannah Klinkhammer, Davide Garzone, Marlene Saßmannshausen, Sarah Thiele, Steffen Schmitz-Valckenberg, Carel Hoyng, Clara I Sánchez, Matthias Schmid, Ulrich F O Luhmann, Heather Floyd, Sergio Leal, Frank G Holz, Robert P Finger

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Abstract

Purpose: The purpose of this study was to analyze genotype-phenotype associations in intermediate age-related macular degeneration (iAMD) based on global and pathway-specific polygenic risk scores (psPRS) in participants of the prospective European multicenter cohort study MACUSTAR.

Methods: Assessed structural biomarkers included reticular pseudodrusen (RPD), pigmentary abnormalities, hyper-reflective foci (HRF), and incomplete or complete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA and cRORA). Blood samples were genotyped and imputed via a local pipeline. Global and pathway-specific PRS (complement PRS [C-PRS], with and without ARMS2/HTRA1 variants [C+AH-PRS and AH-PRS]; extracellular matrix PRS [E-PRS]; and lipid PRS [L-PRS]) were calculated. The associations between global and pathway-specific PRS and structural iAMD biomarkers were assessed with multivariable models, controlling for age and sex.

Results: In total, 404 participants (263 women, 65.1%; mean age = 71.5 ± 7.0 years, mean ± standard deviation [SD]) were included in the analysis. Multivariable regression models revealed that RPD was associated with a higher AH-PRS (estimate = 7.11 × 10-2, P = 9.0 × 10-3), C+AH-PRS (estimate = 9.96 × 10-2, P = 5.0 × 10-3), and E-PRS (estimate = 3.28 × 10-2, P = 3.1 × 10-2). The presence of cRORA was associated with a higher AH-PRS (estimate = 1.34 × 10-1, P = 2 × 10-3) and a higher C+AH-PRS (estimate = 1.59 × 10-1, P = 6 × 10-3).

Conclusions: Structural risk biomarkers are associated with psPRS in iAMD. These findings further underscore the heterogeneity of pathogenic pathways in AMD and indicate differential risk characteristics across the broad spectrum of iAMD.

Translational relevance: Our findings reveal subgroups in iAMD based on genotype-phenotype associations which can help identifying patients at high risk for iAMD and establish new endpoints for clinical trials in iAMD.

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中度年龄相关性黄斑变性的结构表型和多基因风险评分之间的关系——一份MACUSTAR报告。

目的：本研究的目的是基于欧洲前瞻性多中心队列研究MACUSTAR参与者的全局和通路特异性多基因风险评分（psPRS）分析中度年龄相关性黄斑变性（iAMD）的基因型-表型关联。方法：评估的结构生物标志物包括网状假性结节（RPD）、色素异常、高反射灶（HRF）、不完整或完整的视网膜色素上皮（RPE）和视网膜外萎缩（iRORA和cRORA）。血液样本通过当地管道进行基因分型和输入。计算全局和通路特异性PRS（补体PRS [C-PRS]，有或没有ARMS2/HTRA1变体[C+AH-PRS和AH-PRS]，细胞外基质PRS [E-PRS]和脂质PRS [L-PRS]）。通过控制年龄和性别的多变量模型评估全局和通路特异性PRS和结构iAMD生物标志物之间的关联。结果：共纳入404例受试者（女性263例，占65.1%，平均年龄= 71.5±7.0岁，均数±标准差[SD]）。多变量回归模型显示，RPD与较高的AH-PRS（估计值= 7.11 × 10-2, P = 9.0 × 10-3）、C+AH-PRS（估计值= 9.96 × 10-2, P = 5.0 × 10-3）和E-PRS（估计值= 3.28 × 10-2, P = 3.1 × 10-2）相关。cRORA的存在与较高的AH-PRS（估计= 1.34 × 10-1, P = 2 × 10-3）和较高的C+AH-PRS（估计= 1.59 × 10-1, P = 6 × 10-3）相关。结论：结构风险生物标志物与iAMD患者psPRS相关。这些发现进一步强调了AMD致病途径的异质性，并表明了广谱iAMD的不同风险特征。翻译相关性：我们的研究结果揭示了基于基因型-表型关联的iAMD亚群，这有助于识别iAMD高风险患者，并为iAMD临床试验建立新的终点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Vision Science & Technology Engineering-Biomedical Engineering

CiteScore

5.70

自引率

3.30%

发文量

346

审稿时长

25 weeks

期刊介绍： Translational Vision Science & Technology (TVST), an official journal of the Association for Research in Vision and Ophthalmology (ARVO), an international organization whose purpose is to advance research worldwide into understanding the visual system and preventing, treating and curing its disorders, is an online, open access, peer-reviewed journal emphasizing multidisciplinary research that bridges the gap between basic research and clinical care. A highly qualified and diverse group of Associate Editors and Editorial Board Members is led by Editor-in-Chief Marco Zarbin, MD, PhD, FARVO. The journal covers a broad spectrum of work, including but not limited to: Applications of stem cell technology for regenerative medicine, Development of new animal models of human diseases, Tissue bioengineering, Chemical engineering to improve virus-based gene delivery, Nanotechnology for drug delivery, Design and synthesis of artificial extracellular matrices, Development of a true microsurgical operating environment, Refining data analysis algorithms to improve in vivo imaging technology, Results of Phase 1 clinical trials, Reverse translational ("bedside to bench") research. TVST seeks manuscripts from scientists and clinicians with diverse backgrounds ranging from basic chemistry to ophthalmic surgery that will advance or change the way we understand and/or treat vision-threatening diseases. TVST encourages the use of color, multimedia, hyperlinks, program code and other digital enhancements.