Does the Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism modify the response to ACE inhibitor therapy? – A systematic review

University of Zurich, Zürich, Zurich, Switzerland
Current controlled trials in cardiovascular medicine (Impact Factor: 2.33). 11/2005; 6(1):16. DOI: 10.1186/1468-6708-6-16
Source: PubMed


Pharmacogenetic testing to individualize ACE inhibitor therapy remains controversial. We conducted a systematic review to assess the effect modification of the insertion/deletion (I/D) polymorphism of the ACE gene on any outcome in patients treated with ACE inhibitors for cardiovascular and/or renal disease.
Our systematic review involved searching six electronic databases, then contacting the investigators (and pharmaceutical industry representatives) responsible for the creation of these databases. Two reviewers independently selected relevant randomized, placebo-controlled trials and abstracted from each study details on characteristics and quality.
Eleven studies met our inclusion criteria. Despite repeated efforts to contact authors, only four of the eleven studies provided sufficient data to quantify the effect modification by genotypes. We observed a trend towards better response to ACE inhibitors in Caucasian DD carriers compared to II carriers, in terms of blood pressure, proteinuria, glomerular filtration rate, ACE activity and progression to end-stage renal failure. Pooling of the results was inappropriate, due to heterogeneity in ethnicity, clinical domains and outcomes.
Lack of sufficient genetic data from the reviewed studies precluded drawing any convincing conclusions. Better reporting of genetic data are needed to confirm our preliminary observations concerning better response to ACE inhibitors among Caucasian DD carriers as compared to II carriers.

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    • "Although the presence of the D allele appears to negatively affect the course of diabetic nephropathy [13] , while renal outcomes are improved in macroalbuminuric type 2 diabetic individuals with the II genotype [14], a study with 36 Japanese proteinuric patients [15] and another with 83 macroalbuminuric type 2 diabetic Korean patients [16] showed that the effect of ACE inhibition on the severity of proteinuria is more prominent in the presence of the D allele. Caucasian DD carriers appear to show better responses to ACE inhibitors than do II carriers [2]. Finally, a study on 61 proteinuric Dutch patients given short-term ACE inhibition failed to show any effect of genotype on proteinuria. "
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    ABSTRACT: The activity of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the development and progression of diabetic nephropathy. However, the effect of angiotensin-converting enzyme (ACE) inhibition on the RAAS appears to be modulated by a number of factors including the I/D polymorphism of the ACE genotype. In this study, we attempted to find independent correlates of ACE activity in 121 macroalbuminuric type 2 diabetic Iranian patients under chronic ACE inhibition. Both univariate and multivariate analyses were used. The presence of the D allele was independently associated with significantly higher levels of ACE activity (with the II genotype as reference, P < 0.001, B = 27.3, 95% CI = 17.6-37.1), and this association was not eliminated by potentially confounding variables. In conclusion, the D allele is a significant independent correlate of ACE activity in macroalbuminuric type 2 diabetic Iranian patients under long-term ACE inhibition.
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    ABSTRACT: Insertion/deletion polymorphism of the Angiotensin I converting enzyme genetically deter-mines most of the plasma ACE activity. Modulation of ACE gene activity might have an im-portant bearing on the rate of progression of renal disease, though its exact role in the neph-ropathy of Type 2 Diabetes is far from clear. This prospective, cross-sectional, observa-tional study was designed to study correlation between Insertion/Deletion polymorphism of ACE gene in diabetic nephropathy. T2DM cases (n=30) were evaluated, regarding duration, onset and degree of of albuminuria, renal insufficiency and hypertension. All patients un-derwent detailed clinical and biochemical evaluation. Genomic DNA intron 16 of the ACE gene was amplified by polymerase chain reaction (PCR), followed by sequencing. Analysis of variance ANOVA was applied to compare. A p value < 0.05 was considered significant. All calculations were performed using SPSS-11.0. The mean age of this study group was 45.21±2.34 yrs. PCR amplification of ACE gene fragment revealed I/I, (n =8) I/D (n = 18 and D/D (n = 4), alleles.Age wise, all three groups were matched (p=0.012), micro and macro-vascular complications were more prevalent in DD type. Mmajority (75%) of patients with II allele took longer to develop overt albumiuria, having lesser hypertension, renal dysfunc-tion, and dyslipidemia than ID and DD allele (p<0.005). On the other hand, Urinary albu-min excretion (UAE), SBP, DBP, TG, S.Cr. and LDL-C were significantly higher (p<0.005), in patients of DD type than II and ID groups. This finding suggests that patients with DD allele of the ACE gene are more likely to have progressive diabetic nephropathy with most of the micro and macro-vascular complications.
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