Feinberg Cardiovascular and Renal Research Institute (N.K., T.O., P. Leeaw, P. Liu, D.K.D., B.R.T., S.E.Q.), Northwestern University Feinberg School of Medicine, Chicago.
Division of Nephrology and Hypertension (N.K., T.O., P. Leeaw, P. Liu, D.K.D., B.R.T., S.E.Q.), Northwestern University Feinberg School of Medicine, Chicago.
Arterioscler Thromb Vasc Biol. 2024 Oct;44(10):2207-2212. doi: 10.1161/ATVBAHA.124.321555. Epub 2024 Aug 29.
The ANGPT (angiopoietin)-TEK (tyrosine kinase, endothelial) vascular signaling pathway plays a key role in the formation of Schlemm canal, and loss-of-function mutations in the or gene are associated with primary congenital glaucoma in children. In genome-wide association studies, an association was identified between protection from primary open-angle glaucoma and the single-nucleotide polymorphism rs76020419 (G>T), located within a predicted -binding site in the 3' untranslated region of . To date, the functional impact of this variant in the anterior chamber of the eye remains largely unexplored.
MT (mutant) mice harboring an orthologous rs76020419 minor allele (T) were generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9). Plasma and tissue samples, including eyes, were collected, and ANGPT2 expression was quantified using ELISA. Anterior segments from eyes were collected from WT (wild-type) and MT mice, and Schlemm canal area was quantified.
In the MT group, higher ANGPT2 concentrations were observed in the plasma, lungs, kidneys, and eyes (=0.0212, <0.001, =0.0815, and =0.0215, respectively). Additionally, the Schlemm canal was larger in MT mice compared with WT mice (=0.0430).
The rs76020419 minor allele (T) is associated with increased levels of ANGPT2 and a larger Schlemm canal in mice. These findings suggest a potential protective mechanism in glaucoma.
ANGPT（血管生成素）-TEK（酪氨酸激酶，内皮）血管信号通路在施莱姆管的形成中起着关键作用， 或 基因的功能丧失突变与儿童原发性先天性青光眼有关。在全基因组关联研究中，在 3'非翻译区中一个预测的 -结合位点内发现了与原发性开角型青光眼保护相关的单核苷酸多态性 rs76020419（G>T）与 之间的关联。迄今为止，该变体在眼前房的功能影响在很大程度上仍未得到探索。
使用 CRISPR/Cas9（簇状规则间隔短回文重复/簇状规则间隔短回文重复相关 9）生成携带同源 rs76020419 次要等位基因（T）的 MT（突变）小鼠。收集血浆和组织样本，包括眼睛，并使用 ELISA 定量 ANGPT2 表达。从 WT（野生型）和 MT 小鼠收集眼前节，并定量施莱姆管面积。
在 MT 组中，观察到血浆、肺、肾和眼睛中的 ANGPT2 浓度更高（=0.0212，<0.001，=0.0815，和=0.0215，分别）。此外，与 WT 小鼠相比，MT 小鼠的施莱姆管更大（=0.0430）。
rs76020419 次要等位基因（T）与 ANGPT2 水平升高和小鼠施莱姆管增大相关。这些发现表明在青光眼中有潜在的保护机制。
