Association between ACE Gene Polymorphism and Nephropathy in NIDDM Patients

Seo, Jung Kun; Ha, Sung Kyu; Park, Seung Ho; Lee, Chang Hoon; Lee, Seung Yong; Lee, Chang Kyu; Kim, Seung Jung; Park, Chong Hoon; Lee, Ho Yung; Han, Dae Suk

Abstract

It has been reported that the genetic susceptibility may be an important factor in the development of nephropathy in diabetic patients, and the genetic polymorphism of angiotensin-converting enzyme (ACE) has been extensively studied for its possible role. The ACE affects the cardiovascular system through angiotensin II formation and inactivation of bradykinin. The 21 kilobases-long ACE gene located on the long arm of chromosome 17 is composed of 26 exons and 25 introns. The presence/absence of a 287 base pairs fragment in the 16th intron of the ACE gene determines its genotype either as insertion(I) or deletion(D). These genotypes in turn are used to characterize the polymorphism as II, ID or DD type. Each of these genotypes has been reported to show different activity of serum ACE. Recent reports have suggested that genotype DD or D allele may be involved in the nephropathy in diabetics while genotype II may lower the chance for diabetic nephropathy. The present study investigates the effects of genetic polymorphism of ACE on the nephropathy in NIDDM by assessing ACE genotypes and activities on 148 NIDDM patients who have been diagnosed at least 10 years prior to the study, as well as 146 normal controls. The NIDDM group is composed of 70 patients with nephropathy and 78 without nephropathy. The results were as follows. 1) In the diabetic group, the absence/presence of nephropathy showed no significant difference in terms of age, gender, body mass index, HbA1C, cholesterol, triglyceride and HDL cholesterol(p>0.05). No significant differences on the clinical parameters were noted according to the ACE genotypes either(p>0.05). 2) The ratio of ACE genotypes(II:ID:DD) was 0.36:0.48:0.16 for the normal control group, 0.28:0.56: 0.16 for the NIDDM without nephropathy group, and 0.26:0.51:0.23 for the NIDDM with nephropathy group. The ratios of I and D allele were 0.60:0.40, 0.56:0.44 and 0.51:0.49, respectively. In all three groups, higher ratio I allele over D allele was noted and the ID genotype was most frequent followed by II and DD types, although the differences between the groups were not statistically significant(p>0.05). 3) In the normal controls group, ACE activities for DD, ID and II genotypes were 54.0 15.0, 40.4 12.4 and 30.1 11.8U/L, respectively, with significant difference among the genotypes. In the NIDDM without nephropathy group, there was no difference among the three genotypes(DD, ID, II; 47.2 15.1 vs. 36.6 18.7 vs. 32.0 13.4). In the NIDDM with nephropathy group, the activity for DD and ID genotypes were significantly higher than II genotype(47.7 31.0, 47.4 30.7 vs. 17.8 17.9U/L, p<0.05). 4) In the comparison between the patients with normal ACE activity(8-52U/L) and increased ACE activity, no significant differences were noted in terms of body mass index, HbA1C, serum creatinine, HDL cholesterol, 24-hour urinary protein and albumin excretion, creatinine clearance(p>0.05). The results of the present study show that in the normal group genotype ID is most frequent followed by II and DD, and the I allele is more frequent than D allele. These results are similar to the reports from China and Japan, unlike the results from Europe or USA where genotype DD and D allele are more frequent than II genotype and I allele, suggesting an ethnic difference. Furthermore, the NIDDM patients group, regardless of the presence of nephropathy, showed no significant difference from the normal group in terms of ACE genotypes or allele types, suggesting lack of association between the nephropathy and the ACE gene polymorphism. The ACE activity also showed no significant relationship with various clinical parameters or complications. Further studies on the effects of ACE polymorphism and ACE activity on the progression of nephropathy may be needed.