GENETIC PREDISPOSITION TO DIABETIC NEPHROPATHY - EVIDENCE FOR A ROLE OF THE ANGIOTENSIN I-CONVERTING ENZYME GENE

In search of genetic determinants of susceptibility to diabetic nephro pathy, we examined the association between DNA sequence differences at the locus of angiotensin I-converting enzyme (ACE) and renal complica tions in 151 insulin-dependent diabetes mellitus (IDDM) patients with a diabetes duration of 16-21 years. This nested case-control study inc luded 77 normoalbuminuric control subjects (albumin excretion rate <30 mu g/min) and 74 cases with evidence of nephropathy ranging from micr oalbuminuria to overt proteinuria. DNA from each of these patients was genotyped at the ACE locus by a three-allele restriction fragment-mel ting polymorphism (RFMP) (Dde I), which we described recently, and a t wo-allele insertion/deletion recognized as an Xba I restriction fragme nt-length polymorphism, which has been shown by other investigators to be associated with serum levels of ACE and with risk of myocardial in farction. The least common allele of the Dde I RFMP was significantly more frequent among cases with nephropathy than among normoalbuminuric control subjects (12.8 vs. 4.5%, P < 0.05). The deletion in the ACE g ene was also more frequent in case than in control subjects (56.1 vs. 47.4%), but the difference was not statistically significant (P < 0,25 ) with this sample size. To determine the independence of these associ ations, the two polymorphisms were analyzed jointly to identify Xba I/ Dde I haplotypes. As might be expected, carriers of the Xba I/Dde I '=' haplotype had a fourfold risk of developing diabetic nephropathy (o dds ratio [OR] 4.0, 95% confidence interval [CI] 1.5-11.0). However, t his did not explain all of the excess Xba I '+' allele among cases. Ca rriers of the '++' haplotype were also more frequent among cases (OR 2 .0, 95% CI 0.8-4.9), but this association was not statistically signif icant with this sample size. This study provides evidence that DNA seq uence differences in the ACE gene may contribute to genetic susceptibi lity to diabetic nephropathy in IDDM.