Diabetic nephropathy is associated with the greatest morbidity and mortality in IDDM¹⁾. Although the vast majority of diabetic patients have some degree of retinopathy, nephropathy develops in only 35 to 45% of patients with IDDM²⁾, so there is probably a genetic basis for diabetic nephropathy. Previous reports of clustering of diabetic nephropathy in families also provide support for the hypothesis that genetic factors contribute to susceptibility to diabetic nephropathy^3,4).

Angiotensin I converting enzyme (ACE) is a dipeptidase, which has a key role in regulating systemic and renal circulations, activating angiotensin I into the vasoconstrictor peptide angiotensin II, and inactivating the vasodilatory peptide bradykinin⁵⁾. The ACE gene is 21 kilobases long on the chromosome 17 and consists of 26 exons⁶⁾. A genetic polymorphism has been described in intron 16 of the ACE gene⁷⁾. Individuals varied as to the presence (insertion, I) or absence (deletion, D) of a 287 fragment. It has been estimated that the I/D polymorphism accounts for about 47% of the total phenotype variance of serum ACE activity in the normal Caucasian population⁸⁾. Subjects homozygote for the deletion (DD) display the highest values and those homozygote for the insertion (II) display the lowest, with heterozygotes displaying intermediate values. An excess of the DD genotype was recently observed in subjects with myocardial infarction⁹⁾, left ventricular hypertrophy¹⁰⁾ and idiopathic dilated cardiomyopathy¹¹⁾ which suggests that a genetic polymorphism affecting ACE gene expression could be associated with susceptibility to vascular disease.

In Caucasian diabetic patients, it was reported that serum ACE activity is especially elevated in IDDM subjects with microalbuminuria¹²⁾ and II genotype of ACE gene is a marker for reduced risk for diabetic nephropathy¹³⁾. However, I/D allele frequency of ACE gene is known to be different between Caucasian and Oriental normal populations^14,15). The present study was performed to see whether I/D polymorphism of ACE gene is associated with diabetic nephropathy in Korean IDDM patients.

The insertion/large allele (560 bp) is designated I, and the deletion/shorter allele (270 bp) is designated D. Thus, each DNA sample yielded one of three possible genotypes represented as II, ID, and DD (Fig. 1). Frequencies for II, ID and DD genotypes were 23, 19 and 17 in IDDM patients, and 49, 41 and 17 in control subjects, respectively. Derived allele frequencies for I and D alleles were 55.1% and 44.9% in IDDM patients and 64.9% and 35.1% in control subjects, respectively, indicating that there was no significant difference between the two groups (Table 1). In IDDM patients, the subjects with proliferative diabetic retinopathy (PDR) were 11 patients. Frequencies for genotypes of ACE gene were 3, 4 and 4 in subjects with PDR and 20, 15, 13 in subjects without PDR, and derived allele frequencies for I and D alleles were 45.5% and 54.5% in subjects without PDR and 57.3% and 42.7% in subjects without PDR. There was no significant difference between subjects with or without PDR (Table 2).

Talbe 3 gives the clinical characteristics of 31 IDDM cases with nephropathy and 28 IDDM subjects without nephropathy. There was no significant difference in onset age, duration of diabetes and HbAlc level. But the subjects without nephropathy showed a tendency to have a mild degree of retinopathy. Frequencies for II, ID and DD genotypes were 12, 9 and 10 in nephropathy cases and 11, 10 and 7 in cases without nephropathy, and derived allele frequencies for I and D alleles were 53.2% and 46.8% in nephropathy cases and 57.1% and 42.9% in cases without nephropathy. There was no significant difference between IDDM patient with or without nephropathy (Table 4).

The findings of previous epidemiological and family studies suggest that diabetic nephropathy results from an interaction between metabolic abnormalities that are typical of poorly controlled IDDM and predisposing genetic factors^3,4). The nature of the genetic factors, however, has remained unknown. ACE is the component of the renin angiotensin system that catalyzes its inactive precursor angiotensin I. Angiotensin II affects vasoconstriction and sodium retention, alters kidney hemodynamics and increases systemic blood presure¹⁶⁾. A likely possibilty is that the ACE variant acts as a risk factor for diabetic nephropathy by modulating renal hemodynamics without affecting systemic blood pressure, as has been hypothesized for myocardial infarction⁹⁾. In the kidney, ACE mRNA is in endothelial, mesangial and epithelial cells⁶⁾. Other than activating conversion of angiotensin I to angiotensin II, ACE is a component of the intrarenal kallikrein-kinin system, being an inactvatior of bradykinin¹⁶⁾. These two peptides, angiotensin II and bradykinin, have opposite effects on renal circulation. Recently, Marre at al¹³⁾ suggested that II genotype of ACE gene is a marker for reduced risk for diabetic nephropathy in white French IDDM subjects, and Doria et al¹⁷⁾ reported that DNA sequence differences in the ACE gene may contribute to genetic susceptibility to diabetic nephropathy in Caucasian IDDM subjects. Because IDDM has many underlying causes that may be specific to the genetic and cultural background of the patient, racial differences in genetic and etilogical mechanisms are of interest. In the present study, no association was demonstrated, indicating that ACE gene polymorphism is not implicated in the developement of diabetic nephropathy in Korean IDDM patients. It is noteworthy that the frequency of I allele in our normal control subjects, 0.649, was higher than the previously reported values of 0.431 by Tiret et al⁷⁾ and 0.406 by Rigat et al⁸⁾ and was very similar to the value of 0.701 by Lee¹⁴⁾ in Chinese and 0.601 by Higashimori et al¹⁵⁾ in Japanese control subjects. Although these differences may be due to selection bias of normal control subjects, it is most likely to be due to ethnic difference. Contrary to the previous reports, Tarnow et al¹⁸⁾ reported that I/D polymorphism of ACE gene does not act as a risk factor for the development of diabetic nephropathy in Danish IDDM subjects.

We observed that I/D polymorphism of ACE gene is not implicated in the diabetic nephropathy of Korean IDDM patients. Although our sample size is small, our result may be explained by ethnic difference. If the genetic approach has provided new insights into the pathogenesis of diabetic nephropathy, studies involoving various ethnic groups are important.