Association between the ACE I/D gene polymorphism and progressive renal failure in autosomal dominant polycystic kidney disease: A meta-analysis

ObjectiveThe angiotensin converting enzyme insertion/deletion (ACE I/D) gene polymorphism is involved in a wide range of clinical outcomes. This makes ACE I/D an important genetic marker. Updating the genetic profile of ACE I/D and raising the evidence for its role in renal disease is therefore needed. Reported associations of ACE I/D with progressive renal failure (PRF) in autosomal dominant polycystic kidney disease (ADPKD) have been inconsistent, prompting a meta-analysis to obtain more precise estimates.MethodsMulti-database search yielded 18 articles for inclusion in the meta-analysis. Risks (odds ratios [ORs] and 95% confidence intervals) were estimated by comparing the ACE genotypes (heterozygote ID, homozygotes DD and II). Heterogeneous (random-effects) pooled associations were subjected to outlier treatment which yielded fixed-effects outcomes and split the findings into pre- (PRO) and post- (PSO) outlier status. Subgroup analysis was based on ethnicity (Asian/Caucasian) and minor allele frequency (maf). The ≥ 0.50 maf subgroup indicates higher frequency of the variant II genotype over that of the common DD genotype, otherwise, the subgroup is considered < 0.50 maf. Stability of the associative effects was assessed with sensitivity treatment. Temporal trend of association was examined with cumulative meta-analysis.ResultsIn the PSO analysis, overall effects were null (ORs 0.99-1.02) but not in the subgroups (Asian and ≥ 0.50 maf), where in presence of the D allele (DD/ID) and the I allele (II), increased (ORs 1.63-5.62) and reduced (OR 0.22) risks were observed, respectively. Of these pooled effects, the Asian and ≥ 0.50 maf homozygous DD genotypes had high ORs (5.01-5.63) indicating elevated magnitude of effects that were highly significant (Pa < 10−5) and homogeneous (I2 = 0%), in addition to their robustness. In contrast, the Caucasian and < 0.50 maf subgroup effects were: (i) non-heterogeneous (fixed-effects) at the outset, which did not require outlier treatment and (ii) non-significant (ORs 0.91-1.10, Pa = 0.15-0.79). Cumulative meta-analysis revealed increased precision of effects over time.ConclusionsPRF in ADPKD impacted the Asian and ≥ 0.50 maf subgroups where DD homozygote carriers were up to 6-fold susceptible. The high magnitude of these effects were highly significant, homogeneous and robust indicating strong evidence of association.