Relationships between Angiotensin - Converting Enzyme Gene Polymorphism and Initiation and Progression of Renal Failure in Patients with Non-Insulin Dependent Diabetes Mellitus

Lee, Eun Young; Choi, Seung Ok; Chung, Choon Hee

Abstract

OBJECTIVE
Diabetic nephropathy is an important cause of end-stage renal disease and associated with morbidity and mortality of the patients with diabetes mellitus. It has been reported that the genetic susceptibility may be an important factor in the development of nephropathy in diabetic patients, but the genes responsible for the predisposition to diabetic nephropathy are not known. The genes of the renin-angiotensin systems are plausible candidate genes and the genetic polymorphism of angiotensin-converting enzyme(ACE) gene has been extensively studied for its possible role. Recently, the association of the ACE gene polymorphism with nephropathy as well as myocardial infartion was reported in diabetic patients. To elucidate the contribution of ACE gene polymorphism to the initiation and progression of diabetic nephropathy, we typed the alleles of the ACE gene in 139 patients with non-insulin dependent diabetes mellitus (NIDDM).
METHODS
After the extraction of genomic DNA from peripheral blood leukocytes, PCRs were performed using the flanking and insertion specific primers, respectively. The PCR products were electrophoresed in 1.5% agarose gels, and DNA was visualized directly with ethidium bromide staining. RESULTS: Subjects were consisted of 139 patients with diabetes mellitus and male to female ratio was 63:76, mean age 55.8+/-12.0 years, mean duration of diabetes 9.5+/-7.8 years. ACE genotypes in whole population were 37.4% DD genotype, 51.1% ID genotype and 11.5% II genotype. The ACE genotype distributions, age, sex, blood pressure and body mass index were not different in diabetic subjects with or without nephropathy. No significant differences on the clinical parameters such as age, sex, blood pressure, body mass index, duration of diabetes, incidence of hypertension, cardiovascular complication, diabetic neuropathy and retinopathy, serum creatinine and 24hour albumin excretion were noted according to the ACE genotypes. Forty-six patients with NIDDM were followed over 3 years. The mean follow-up duration was 6.4+/-2.7 years, mean age was 54.4+/-10.2 years, and mean duration of diabetes was 14.7+/-6.1 years. ACE genotypes were 36.9% DD genotype, 52.2% ID genotype and 10.9% II genotype. The ACE genotype distributions were not different in the patients among DD, II or II genotypes. There were also no significant differences in terms of age, sex, duration of diabetes, blood pressure, body mass index, prevalence of hypertension, cardiovascular complication, diabetic neuropathy and diabetic retinopathy. But the rate of decline of creatinine clearance(deltacreatinine clearance, ml/min/year) was higher in DD genotype than ID or II genotypes(3.3+/-7.2 vs 2.8+/-6.2 vs 2.7+/-9.8), and the rate of change of 24-hour protein excretion(deltaurinary protein excretion, mg/24hours/year) was higher in DD genotype than ID or II genotypes(89.3+/-220.0 vs 74.1+/-156.8 vs 70.9+/-546.3). But they did not reach to statistical significance.
CONCLUSION
We found that insertion/deletion polymorphism of ACE gene is not implicated in the initiation of diabetic nephropathy of Korean NIDDM patients, but also found the possibility that progression of diabetic nephropathy may be associated with it. We need large scaled prospective follow-up studies on the effects of ACE polymorphism in the progression of diabetic nephropathy.