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Abstract #121250 Published in IGR 25-1
Glaucoma-Protective Human Single-Nucleotide Polymorphism in the Locus Increased ANGPT2 Expression and Schlemm Canal Area in Mice-Brief Report
Kiyota N; Onay T; Leeaw P; Liu P; Deb DK; Thomson BR; Segrè AV; Segrè AV; Wiggs JL; Quaggin SEArteriosclerosis, thrombosis, and vascular biology 2024; 44: 2207-2212
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
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