Association of the KCNJ11 E23K (rs5219) variant with proliferative diabetic retinopathy in Lebanese patients with type 2 diabetes
TL;DR
In this Middle Eastern population, KCNJ11 E23K showed a stage-specific association with prevalent proliferative, vision-threatening DR rather than with earlier stages of retinopathy, supporting the potential utility of E23K as a marker of advanced retinopathy severity, although longitudinal studies in diverse ethnic groups are required to determine its relationship with disease progression.
Abstract
Background ATP-sensitive potassium channels regulate insulin release, with the KCNJ11 gene encoding the Kir6.2 channel’s pore subunit. The E23K variant, previously linked to type 2 diabetes (T2DM), was examined in a large Lebanese cohort to determine its relationship to diabetic retinopathy (DR) severity and glycemic control. Methods A case–control sample of 1,415 adults with T2DM were classified as diabetes without retinopathy (DWR; n = 933), non-proliferative DR (NPDR; n = 342), or proliferative DR (PDR; n = 140) based on ETDRS criteria, and compared with 1,389 normoglycemic controls. Logistic regression was used to assess genetic associations across multiple inheritance models. Sensitivity analyses stratified by diabetes duration and area under the ROC curve (AUC) compared discrimination using age and sex, with or without genotype. Results The K allele was more frequent in T2DM than in controls. Although E23K was not associated with overall DR, its effect was stage-specific. In comparisons of PDR with DWR, each additional K allele increased PDR odds, and K/K homozygosity showed a stronger recessive effect. The K/K genotype was notably enriched among DR patients with HbA1c ≤ 7.0%, indicating an elevated risk under good glycemic control, but showed no signal in those with poorer control. It was also overrepresented in PDR. Risk associations were more pronounced in individuals with diabetes duration ≥10 years, and adding genotype information resulted in a small increase in model discrimination beyond age and sex alone (AUC = 0.552–0.598; ΔAUC = 0.046). However, the overall discriminatory performance remained poor, suggesting limited clinical utility of E23K genotyping as an isolated predictive marker. Conclusion In this Middle Eastern population, KCNJ11 E23K showed a stage-specific association with prevalent proliferative, vision-threatening DR rather than with earlier stages of retinopathy. This supports the potential utility of E23K as a marker of advanced retinopathy severity, although longitudinal studies in diverse ethnic groups are required to determine its relationship with disease progression.