IS THE PRESENCE OF RETINOPATHY OF PRACTICAL VALUE IN DEFINING CASES OF DIABETIC NEPHROPATHY IN GENETIC ASSOCIATION STUDIES? THE EXPERIENCE WITH THE ANGIOTENSIN-I CONVERTING ENZYME I/D POLYMORPHISM BASED ON 53 STUDIES COMPRISING 17,791 SUBJECTS

Abstract

Objective: A key consideration when setting up genetic studies is the case definition. For diabetic nephropathy (DN), the case definition is typically defined based on the presence of albuminuria. However, it has been long debated whether DN cases defined in this way may have a high prevalence of non-diabetic kidney disease especially if diabetic retinopathy (DR) is absent.

Research Design and Methods: We performed a meta-analysis of 53 studies comprising 17,791 subjects investigating the angiotensin-I converting enzyme insertion/deletion (I/D) polymorphism, taking into account the requirement for DR in the case definition and assuming a random effects model.

Results: No publication bias was observed. The overall pooled odds ratio (OR) for all 53 studies was 0.78 (95%CI=0.70–0.87, P<0.001) which indicated a significant protection against DN for genotype II as compared with carriage of the D allele. The pooled OR for the 11 studies (n = 3,413) requiring DR in the case definition was 0.68 (95%CI=0.53-0.86, P=0.002) and this was not significantly different from the pooled OR of 0.81 (95%CI=0.71-0.92, P=0.001) obtained from the 42 remaining studies (n = 14,378) (P=0.198). This lack of any significant effect of DR was reiterated in subgroup analyses according to the type of diabetes present.

Conclusions: Stipulating the presence of DR in the case definition of DN did not appear to confer tangible benefits when detecting genetic associations. Besides reducing sample sizes, this stipulation makes the interpretation of genetic associations more difficult due to the potential confounding presence of DR.