From the Division of BioMedical Sciences (H.P., S.W., G.Z., R.L.G., R.T.), Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada.
Smith Kettlewell Eye Research Institute (M.M., W.V.G.), San Francisco, California, USA.
Am J Ophthalmol. 2024 Jul;263:179-187. doi: 10.1016/j.ajo.2023.12.017. Epub 2024 Jan 14.
There is strong evidence that genetic factors influence retinopathy of prematurity (ROP), a neovascular eye disease. It has been previously suggested that polymorphisms in the genes involved in β-adrenergic receptor (ADRβ) pathways could protect against ROP. Antagonists for the ADRβ are actively tested in clinical trials for ROP treatment, but not without controversy and safety concerns. This study was designed to assess whether genetic variations in components of the ADRβ signaling pathways associate with risk of developing ROP.
An observational case-control targeted genetic analysis.
A study was carried out in premature participants with (n = 30) or without (n = 34) ROP and full-term controls (n = 20), who were divided into a discovery cohort and a validation cohort. ROP was defined using International Classification of Retinopathy of Prematurity criteria (ICROP). Targeted sequencing of 20 genes in the ADRβ pathways was performed in the discovery cohort. Polymerase chain reaction (PCR)/restriction enzyme analysis for some of the discovered ROP-associated variants was performed for validation of the results using the validation cohort.
The discovery cohort revealed 543 bi-allelic variants within 20 genes of the ADRβ pathways. Ten single-nucleotide variants (SNVs) in 5 genes including protein kinase A regulatory subunit 1α (PRKAR1A), rap guanine exchange factor 3 (RAPGEF3), adenylyl cyclase 4 (ADCY4), ADCY7, and ADCY9 were associated with ROP (P < .05). The most significant SNV was found in PRKAR1A (P = .001). Multiple variants located in the 3'-untranslated region (3'UTR) of RAPGEF3 were also associated with ROP (P < .05). PCR/restriction enzyme analysis of the 3'UTR of RAPGEF3 methodologically validated these findings.
SNVs in PRKAR1A may represent protective factors whereas SNVs in RAPGEF3 may represent risk factors for ROP. PRKAR1α has previously been implicated in retinal vascular development whereas the RAPGEF3 product has a role in the maintenance of vascular barrier function, 2 processes important in ROP. Multicenter validation of these newly discovered risk factors could lead to valuable tools for predicting and preventing the development of severe ROP.
有强有力的证据表明遗传因素会影响早产儿视网膜病变（ROP），这是一种新生血管性眼病。先前有研究表明，β-肾上腺素能受体（ADRβ）途径相关基因的多态性可能对 ROP 有保护作用。ADRβ 拮抗剂目前正在临床试验中积极用于 ROP 的治疗，但也存在争议和安全性问题。本研究旨在评估 ADRβ 信号通路成分的遗传变异是否与 ROP 的发病风险相关。
一项针对观察性病例对照的靶向基因分析。
本研究纳入了有（n=30）或无 ROP（n=34）的早产儿以及足月对照组（n=20）参与者，这些参与者被分为发现队列和验证队列。ROP 采用国际早产儿视网膜病变分类标准（ICROP）进行定义。在发现队列中对 ADRβ 途径中的 20 个基因进行靶向测序。对一些与 ROP 相关的发现变体使用聚合酶链反应（PCR）/限制性内切酶分析在验证队列中进行验证。
发现队列在 ADRβ 途径的 20 个基因中发现了 543 个双等位基因变异。5 个基因中的 10 个单核苷酸变异（SNV），包括蛋白激酶 A 调节亚基 1α（PRKAR1A）、Rap 鸟嘌呤交换因子 3（RAPGEF3）、腺苷酸环化酶 4（ADCY4）、ADCY7 和 ADCY9，与 ROP 相关（P<0.05）。PRKAR1A 中的最显著 SNV 与 ROP 相关（P=0.001）。RAPGEF3 3'非翻译区（3'UTR）中多个位于的 SNV 也与 ROP 相关（P<0.05）。RAPGEF3 3'UTR 的 PCR/限制性内切酶分析从方法学上验证了这些发现。
PRKAR1A 中的 SNV 可能代表保护因素，而 RAPGEF3 中的 SNV 可能代表 ROP 的风险因素。PRKAR1α 先前已被牵涉到视网膜血管发育中，而 RAPGEF3 产物在维持血管屏障功能中发挥作用，这两个过程在 ROP 中都很重要。对这些新发现的风险因素进行多中心验证可能会为预测和预防严重 ROP 的发生提供有价值的工具。
