Investigating therapeutic response to netarsudil in glaucoma subjects with the ARHGEF12 risk variant

ARHGEF12 variants, which regulate the RhoA/ROCK pathway, are associated with primary open-angle glaucoma (POAG) in individuals of African ancestry and may influence response to Rho-kinase inhibitors such as netarsudil.

We analyzed 1,844 African ancestry subjects with POAG, comparing baseline demographic and ocular phenotypes across ARHGEF12 genotype groups (non-carriers, heterozygous carriers, and homozygous carriers). Netarsudil response was evaluated in a subset of 66 subjects (114 eyes). Generalized estimating equations were used to compare the change in intraocular pressure (IOP) and other ocular measures from baseline to 12 months across the ARHGEF12 genotype groups.

Baseline glaucoma severity and ocular phenotypes including IOP were similar across all ARHGEF12 genotype groups (all p > 0.05). Among netarsudil-treated eyes, mean IOP reduction at 12 months was -1.77 ± 5.06 mmHg (SD) in non-carriers and 1.58 ± 6.25 mmHg (SD) in combined heterozygous/homozygous carriers. A ≥20% IOP reduction at 12 months was achieved in 29.8% of non-carrier eyes and 34.6% of variant-carrier eyes (aOR 1.31, 95% CI 0.42-4.10, p = 0.64). Among the netarsudil treated eyes, no statistically significant differences were observed across genotype groups for other ocular measures, including cup-to-disc ratio, retinal nerve fiber layer thickness, and visual field mean deviation.

Despite a strong biological rationale linking ARHGEF12 to Rho/ROCK signaling and aqueous humor outflow, these preliminary findings suggest that ARHGEF12 variant status does not strongly predict netarsudil response, suggesting that variability in ROCK inhibitor efficacy likely reflects multifactorial and pathway-level influences beyond single-gene variation. These results should therefore be considered exploratory. Future studies with larger, treatment-naïve cohorts are needed to evaluate pharmacogenetic associations.