Potential influence of carbonic anhydrase 9 genetic variants and expression levels on the progression of diabetic retinopathy

Diabetic retinopathy (DR) represents one of the most common microvascular complications of diabetes, and proliferative diabetic retinopathy (PDR) is the most vision-threatening form. Carbonic anhydrase IX (CA9), a hypoxia-inducible enzyme, has been implicated in several pathological processes, but its involvement in DR has not been clarified. In this study, three CA9 single nucleotide polymorphisms (rs3829078, rs2071676, and rs1048638) were genotyped in diabetic patients with and without DR. Clinical characteristics were compared between groups, and expression analyses were conducted using public databases and ARPE-19 cells under hyperglycemic and hypoxic conditions. No significant association was observed between CA9 variants and DR susceptibility in the overall cohort. However, among patients aged ≤60 years, carriers of the rs1048638 C/A and C/A + A/A genotypes exhibited a significantly increased risk of PDR. Expression quantitative trait locus (eQTL) data from the GTEx database revealed higher CA9 mRNA expression in tissues harboring the rs1048638 A allele. Moreover, both transcriptomic data and in vitro experiments demonstrated upregulation of CA9 in ARPE-19 cells exposed to high glucose and hypoxia. These findings suggest that the rs1048638 polymorphism may modulate CA9 expression and contribute to PDR development in younger diabetic patients through hypoxia-and glucose-related mechanisms. Collectively, our findings suggest that CA9 may serve as a potential risk biomarker associated with the progression of DR, particularly in younger patients.