Wang et al. (1) recently examined aldose reductase as a susceptibility gene for diabetic nephropathy among type 2 diabetic Chinese in Hong Kong. Although there was a small increase in the frequencies of the risk alleles of the (CA)n dinucleotide repeat and C-106T polymorphisms, analysis of the genotype distribution failed to detect any significant association between these polymorphisms and diabetic nephropathy (1). This negative result persisted despite confining the statistical analyses to control subjects who were normoalbuminuric with at least 5 years of known diabetes duration and case subjects with both diabetic nephropathy and concomitant diabetic retinopathy.

By and large, this study does not confirm earlier findings, which had implicated aldose reductase as a genetic risk factor for diabetic nephropathy among Caucasians with type 1 diabetes (2). Although the two studies were done on patients with different types of diabetes, drawn from separate human populations, which may arguably provide a basis for the discordant findings, a distinct possibility relates to the differential definitions of diabetic nephropathy. In this Boston study, diabetic nephropathy was defined on the basis of persistent proteinuria, i.e., ≥1+ on Multistix or albumin-to-creatinine ratio (ACR) ≥300 mg/g, or end-stage renal disease due to diabetic nephropathy (2). In contrast, the definition used in the current Hong Kong study was less stringent and included patients with microalbuminuria (albumin excretion rate ≥20 μg/min or ACR ≥3.5 g/mmol) (1). This latter criterion poses some concern in terms of misclassification because regression of micro- to normoalbuminuria is likely to be a common phenomenon, as recently demonstrated in type 1 diabetic patients (3). In genetic epidemiological studies, such misclassification can diminish the power of a study to detect an association. Therefore, the study by Wang et al. does not negate the hypothesis that aldose reductase could be a susceptibility gene for advanced diabetic nephropathy in type 2 diabetes. This possibility might be addressed by reanalyzing their data using a stricter definition based on advanced diabetic nephropathy.

Wang Y, Ng MC, Lee SC, So WY, Tong PC, Cockram CS, Critchley JA, Chan JC: Phenotypic heterogeneity and associations of two aldose reductase gene polymorphisms with nephropathy and retinopathy in type 2 diabetes.
Diabetes Care
Moczulski DK, Scott L, Antonellis A, Rogus JJ, Rich SS, Warram JH, Krolewski AS: Aldose reductase gene polymorphisms and susceptibility to diabetic nephropathy in type 1 diabetes mellitus.
Diabet Med
Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS: Regression of microalbuminuria in type 1 diabetes.
N Engl J Med