Doctor Daniel P.K. Ng (1) was surprised by our reporting of a higher incidence of end-stage renal failure (ESRD) among the participants of the Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) study with the ACE II genotype than among those without the genotype given that he had published a large, case-control–based meta-analysis supporting the idea that this genotype protects people with diabetes against the risk (2). We were surprised as well, and we were not able to replicate the results in another prospective follow-up study of type 2 diabetic subjects (the Survie, Diabete de type 2 et Genetique [SURDIAGENE] study). Our report highlights two notions regarding potentially harmful genotypes and ESRD: first, the need to replicate one finding for validation, and second, the interest of assessing the value of genotype on a prospective, follow-up basis. We noticed in DIABHYCAR that prior myocardial infarction was more frequent in the ACE II participants at baseline, whereas this genotype protected against death after myocardial infarction during the study (3). Thus, the ACE insertion/deletion (I/D) genotype may not be neutral for type 2 diabetic subjects. Risk of death is much higher than risk of ESRD for these subjects (4). Interestingly, Parving et al. noticed a high proportion of II genotypes among the black participants in a study on renal prognosis, whereas this genotype is infrequent in that ethnicity (5).
Ng also suggested that the haplotype-based genetic structure should be studied. We agree with this proposal, although the I/D polymorphism proved to be as informative as the haplotype-based approach in type 1 diabetic patients (6). Finally, our study focused on the ACE I/D polymorphism because it is the most widely studied in diabetic renal complications. We thus developed a practical evaluation of its associations.
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