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MMP9 Genotype and Systemic T-Cell Subsets Correlate With Structural and Functional Outcomes in Neovascular Age-Related Macular Degeneration
Journal article   Open access   Peer reviewed

MMP9 Genotype and Systemic T-Cell Subsets Correlate With Structural and Functional Outcomes in Neovascular Age-Related Macular Degeneration

Thomas L Martinez, Zeb R Zacharias, Kyungmoo Lee, Ian C Han, Chunhua Jiao, Bernardo B Bach, Benjamin Roos, Srinivas Chava, Mary M McCormick, Christine Sinkey, …
Investigative ophthalmology & visual science, Vol.67(6), 29
06/01/2026
DOI: 10.1167/iovs.67.6.29
PMCID: PMC13281956
PMID: 42300675
url
https://doi.org/10.1167/iovs.67.6.29View
Published (Version of record) Open Access

Abstract

Genetic studies implicate the matrix metalloproteinase-9 (MMP9) locus in neovascular age-related macular degeneration (nvAMD) risk but genotype-phenotype associations of MMP9 with nvAMD are lacking. This study aimed to investigate the influence of MMP9 genotype and T-cell subset frequency on structural and functional treatment outcomes in nvAMD.PurposeGenetic studies implicate the matrix metalloproteinase-9 (MMP9) locus in neovascular age-related macular degeneration (nvAMD) risk but genotype-phenotype associations of MMP9 with nvAMD are lacking. This study aimed to investigate the influence of MMP9 genotype and T-cell subset frequency on structural and functional treatment outcomes in nvAMD.We reanalyzed single-cell RNA sequencing data and used ELISA and flow cytometry in THP-1-derived monocytes to measure immune cell expression of MMP9 within human choroids. In a clinical nvAMD cohort of 38 patients, we genotyped the nvAMD risk single nucleotide polymorphism (SNP; rs4810482) and quantified retinal fluid using deep-learning-based optical coherence tomography (OCT) image analysis. On a subset of nine patients, we performed high-dimensional immunophenotyping.MethodsWe reanalyzed single-cell RNA sequencing data and used ELISA and flow cytometry in THP-1-derived monocytes to measure immune cell expression of MMP9 within human choroids. In a clinical nvAMD cohort of 38 patients, we genotyped the nvAMD risk single nucleotide polymorphism (SNP; rs4810482) and quantified retinal fluid using deep-learning-based optical coherence tomography (OCT) image analysis. On a subset of nine patients, we performed high-dimensional immunophenotyping.MMP9 is predominantly expressed in mature THP-1-derived dendritic-like cells (ELISA, P = 0.009; flow cytometry, P = 0.001). Patients with the TC genotype of MMP9 exhibited greater disease severity compared to CC or TT genotypes with a significantly higher total retinal fluid volume (P = 0.009). Immunophenotyping revealed that higher proportions of circulating CD8+ effector memory T cells re-expressing CD45RA (TEMRA) were associated with increased residual subretinal fluid (P = 0.03), indicating persistent disease activity.ResultsMMP9 is predominantly expressed in mature THP-1-derived dendritic-like cells (ELISA, P = 0.009; flow cytometry, P = 0.001). Patients with the TC genotype of MMP9 exhibited greater disease severity compared to CC or TT genotypes with a significantly higher total retinal fluid volume (P = 0.009). Immunophenotyping revealed that higher proportions of circulating CD8+ effector memory T cells re-expressing CD45RA (TEMRA) were associated with increased residual subretinal fluid (P = 0.03), indicating persistent disease activity.MMP9 genotype affects structural and functional outcomes in patients with nvAMD. Along with the observed systemic immune dysregulation, these findings support the role of a MMP9-dendritic-T-cell axis in nvAMD immunopathogenesis and highlight this as a potential therapeutic target.ConclusionsMMP9 genotype affects structural and functional outcomes in patients with nvAMD. Along with the observed systemic immune dysregulation, these findings support the role of a MMP9-dendritic-T-cell axis in nvAMD immunopathogenesis and highlight this as a potential therapeutic target.

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