OBJECTIVE: A familial predisposition was proposed to be a determinant of the increased morbidity and mortality from cardiovascular disease in type 1 diabetic patients with diabetic nephropathy. The insertion allele of an insertion/deletion polymorphism in the ACE (ACE/ID) gene seems to protect against coronary heart disease in nondiabetic and diabetic subjects. The aim of the present study was to evaluate these hypotheses in parents of a large group of type 1 diabetic patients with and without diabetic nephropathy. RESEARCH DESIGN AND METHODS: We investigated cardiovascular morbidity and mortality of parents of 163 type 1 diabetic patients with nephropathy and parents of 163 sex- and age-matched normoalbuminuric patients with type 1 diabetes. RESULTS: Kaplan-Meier curves showed that total parental mortality was significantly increased in parents of type 1 diabetic patients with nephropathy (121 of 244 [ approximately 50%] ) as compared with parents of normoalbuminuric type 1 diabetic patients (119 of 269 [approximately 44%]) (P = 0.008 [log-rank test]) partially due to an increase in cardiovascular deaths (48 of 244 [approximately 20%] vs. 42 of 269 [approximately 16%], P<0.05). In addition, more patients with nephropathy, as compared with the normoalbuminuric group, had at least one parent with fatal/nonfatal cardiovascular disease (46% [95% CI 38-54] vs. 36% [28-44], P = 0.05). Fathers of patients homozygous for the I-allele of the ACE/ID polymorphism had significantly less myocardial infarction as compared with other genotypes (P = 0.03), regardless of the nephropathic state of the offspring. CONCLUSIONS: Cardiovascular morbidity and early mortality clusters in parents of type 1 diabetic patients with diabetic nephropathy The ACE/ID polymorphism helps explain the increased morbidity from cardiovascular disease.

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