Aldose reductase genotypes and cardiorenal complications: an 8-year prospective analysis of 1,074 type 2 diabetic patients

Abstract

Objective: We report the independent risk association of type 2 diabetic nephropathy with the z-2 allele of the 5'-(CA)(n) microsatellite and C-106T promoter polymorphisms of the aldose reductase gene (ALR2) using a case-control design. In this expanded cohort, we examined their predictive roles on new onset of cardiorenal complications using a prospective design.

Research design and methods: In this 8-year prospective cohort of 1,074 type 2 diabetic patients (59% male, median age 61 years; disease duration 7 years) with an observation period of 8,592 person-years, none had clinical evidence of coronary heart disease (CHD) or chronic kidney disease at recruitment. The renal end point was defined as new onset of estimated glomerular filtration rate <60 ml/min per 1.72 m(2) or hospitalizations with dialysis or death due to renal disease, and CHD was defined as hospitalizations with myocardial infarction, ischemic heart disease, or related deaths.

Results: After controlling for baseline risk factors and use of medications, we found that the ALR2 z-2 allele of (CA)(n) microsatellite carriers had increased risk of renal (hazard ratio 1.53 [95% CI 1.14-2.05], P = 0.005) or combined cardiorenal (1.31 [1.01-1.72], P = 0.047) end points. Carriers of the ALR2 C-106T polymorphism also had increased risk of renal (1.54 [1.15-2.07], P = 0.004) and cardiorenal (1.49 [1.14-1.95], P = 0.004) end points. Compared with noncarriers, patients with two risk-conferring genotypes had a twofold increased risk of renal (2.41 [1.57-3.70], P < 0.001) and cardiorenal (1.94 [1.29-2.91], P = 0.002) end points.

Conclusions: In Chinese type 2 diabetic patients, genetic polymorphisms of ALR2 independently predicted new onset of renal and cardiorenal end points, with the latter being largely mediated through renal disease.

Figure 1

Cumulative incidence of renal end point stratified by the number of risk alleles of the z−2 allele of the 5′-(CA)_n microsatellite and C-106T promoter polymorphisms of the ALR2 gene (P_trend = 0.003, log-rank test) in type 2 diabetes. +ve, positive; -ve, negative.

Figure 2

Cumulative incidence of cardiorenal end point stratified by the number of risk alleles of the z−2 allele of the 5′-(CA)_n microsatellite and C-106T promoter polymorphisms of the ALR2 gene (P_trend 0.002, log-rank test) in type 2 diabetes. +ve, positive; -ve, negative.