Glaucoma is one of the leading causes of irreversible blindness globally, affecting nearly 95 million individuals, with approximately 10 million suffering from complete vision loss. The pathogenesis of glaucoma is complex and not yet fully understood, often implicates multiple risk factors including elevated intraocular pressure (IOP) and increasingly, inflammation. A recent study published on March 14, 2025, lends new insights by employing Mendelian randomization (MR) to probe the connections between inflammatory proteins and glaucoma risk.
Researchers, led by W. Xu, Q. Fan, Y. Meng, and their team, analyzed data from 91 inflammatory proteins to determine their potential associations with glaucoma conditions, particularly focusing on primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). Utilizing large genomic data sets combined with MR, the study's intent was to ascertain causal relationships and enrich the existing knowledge surrounding glaucoma's pathology.
The MR analysis included up to 14,824 participants for circulating protein levels and was supported by data from the 10th round of the FinnGen GWAS database involving 412,181 European participants. After thorough analysis, the researchers found seven out of 91 inflammatory proteins with potential relationships to glaucoma risk. Among these, T-cell surface glycoprotein CD5 (CD5) stood out, demonstrating protective effects against POAG, with findings indicating it significantly reduced glaucoma risk (odds ratio = 0.87).
"This study, to our knowledge, is the first to systematically explore the potential causal relationship between 91 circulating inflammatory proteins and glaucoma using MR," wrote the authors of the article. This novel approach allowed them to not only identify potential causative agents but also explore how certain endophenotypes—like IOP—mediated these effects. The mediation analysis indicated IOP played a significant role, explaining approximately 38.3% of CD5’s protective effect against POAG.
While the relationship between CD5 and glaucoma was highlighted, findings concluded it conferred protective effects primarily against POAG, with no significant association to PACG. This specificity suggests therapeutic potential for CD5 targeting, which could become instrumental for POAG treatment strategies. Further investigation will be required to elucidate the underlying mechanisms of CD5's protective role, particularly how it may affect inflammatory pathways linked to glaucomatous damage.
Past studies have indicated elevated systemic inflammatory markers in glaucoma patients, hinting at inflammation's potential role as more than just a response to optic nerve damage. Prior research showed lower serum levels of CD5 were present among glaucoma patients, aligning with this new analysis' results. The integration of genetic epidemiological tools like MR offers advances over traditional observational studies, as they effectively minimize uncertainties related to confounding factors and reverse causation.
Boasting unique strengths, this study utilized MR methodology, effectively simulating randomized controlled trials to enrich causal inference and outcome analysis. Future explorations of CD5’s therapeutic potential could drive advancements not only for POAG but for the broader spectrum of glaucoma, as the relationship between immune response and ocular health becomes increasingly clear.
Concluding, the compelling evidence from this study suggests circulating CD5 is linked to lower risks of POAG, pointing to innovative treatment avenues focused on inflammation modulation. With IOP-lowering treatments still remaining pivotal for glaucoma management, targeted CD5 therapies may provide complementary approaches to safeguarding vision among patients suffering from POAG. Researchers are hopeful about future studies exploring how circulating CD5 influences glaucoma risk and whether therapies targeting this protein could usher new strategies to combat this pervasive sight-stealing disease.