Cytokine Gene Polymorphisms in Primary Glaucoma: Insights into Inflammatory Pathways and Future Directions

Glaucoma is a leading cause of irreversible blindness worldwide. A substantial proportion of patients experience disease progression despite adequate IOP control, which is the most significant modifiable risk factor. This indicates the involvement of additional pathogenic mechanisms. One such mechanism is neuroinflammation within the retina and optic nerve head, spearheaded by resident glial cells. These activated glial cells initiate a cascade of proinflammatory cytokines that drives oxidative stress, excitotoxic injury, and ultimately apoptosis in retinal ganglion cells (RGCs), the cells that are responsible for vision. Given the central role of cytokines in mediating this neuroinflammatory damage, several genetic association studies have checked whether functional variants in the cytokine genes modify disease susceptibility to primary glaucoma. In this review, we critically compare and assess the strength of these associations in both open-angle and angle-closure glaucoma, highlighting the inconsistencies and population-specific variability, while also evaluating the limitations of current association studies and how to overcome these challenges. Second, we address a critical mechanistic gap-how cytokine gene variants may influence glial activation, and contribute to the inflammatory ocular microenvironment that may drive disease progression. Finally, we discuss if oxidative stress-driven epigenetic modifications may modulate cytokine gene expression and amplify inflammatory responses in individuals who might be genetically predisposed to develop primary glaucoma.