The Role of AKR1B1 in Diabetic Nephropathy: A Genetic Association Study and Meta-Analysis

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus with a strong genetic component. The aldo-keto reductase family 1 member B (AKR1B1) gene has been implicated in hyperglycemia-induced renal damage. This study aimed to investigate the association between AKR1B1 variants and DN through a genetic association study (GAS) and a comprehensive meta-analysis.

A case-control study was conducted in a Greek population, including 190 DN patients, 150 T2DM patients without nephropathy, and 238 healthy controls. Five tagging single-nucleotide polymorphisms (SNPs) in AKR1B1 were genotyped. Associations were assessed using the generalized odds ratio (OR_G). A systematic literature search was performed, and eligible studies were included in a meta-analysis using a random-effects model.

In the case-control study, none of the examined SNPs showed a significant association with DN in any comparison model. However, meta-analysis results demonstrated a significant association for the promoter variant -106 C>T (rs759853) in diabetic individuals without nephropathy versus DN cases (OR_G = 1.389, 95% CI: 1.134-1.700). The (CA)n polymorphism showed a non-significant overall effect but was associated with increased risk in subgroups of Asians (OR_G = 1.455, 95% CI: 1.042-2.032) and T2DM patients (OR_G = 1.357, 95% CI: 1.039-1.771). No associations were observed when healthy controls were used.

While no significant associations were detected in the single-cohort analysis, meta-analytic evidence supports a role of regulatory AKR1B1 variants in DN susceptibility. These findings highlight the importance of control selection and suggest that AKR1B1 may influence progression to nephropathy rather than diabetes risk per se.