Abstract

Background: We reported the independent risk association of type 2 diabetic nephropathy with z-2 allele of the 5′–(CA)_n microsatellite and C–106T promoter polymorphisms of the aldose reductase (ALR2) gene using case-control design. In this expanded cohort, we examined their predictive roles on new onset of cardio-renal complications using a prospective design.

Methods: In this 8-year prospective cohort of 1074 type 2 diabetic patients (59% male, median age: 61 years; disease duration: 7 years) with an observation period of 8592 person-years, none had clinical evidence of coronary heart disease (CHD) or chronic kidney disease (CKD) at recruitment. Renal endpoint was defined as new onset of estimated glomerular filtration rate (eGFR) < 60 min/min/1.72m², hospitalizations with dialysis or death due to renal disease while 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, ALR2 z-2 allele of (CA)_n microsatellite carriers had increased risk of renal [hazard ratio, 1.53; 95 percent confidence interval, (1.14-2.05) p=0.005] or combined cardio-renal endpoints [1.31 (1.01-1.72) p=0.047]. Carriers of ALR2 C-106T polymorphism also had increased risk of renal [1.54(1.15-2.07) p=0.004] and cardio-renal endpoint [1.49 (1.14-1.95) p=0.004]. Compared to non-carriers, patients with 2 risk conferring genotypes had 2-fold increased risk of renal [2.41 (1.57-3.70) p<0.001] and cardio-renal endpoints [1.94 (1.29-2.91) p=0.002].

Conclusions: In Chinese type 2 diabetic patients, genetic polymorphisms of the ALR2 independently predict new onset of renal and cardio-renal endpoints, the latter largely mediated through renal disease.