Based on our systematic review, evidence quantifying the extent of effect modification related to the I/D polymorphism is sparse. We did note a trend towards better response to ACE inhibitor therapy in DD Caucasians as compared to II carriers, who seemed not to benefit.
The strengths of this review include the comprehensive literature search and strict adherence to systematic review methodology. We restricted our analyses to trials with placebo controls, as studies without a placebo control group do not allow for estimation of the ACE inhibitor effect and are likely to be confounded [35
Although we identified 11 randomised controlled trials that assessed differences in treatment effects among genotypes, only the results of four trials studying 925 patients contributed to our analyses. The authors of the remaining seven studies that included 577 patients did not provide data about genetic subgroups in the intervention and control arms [26
]. Others presented combined results for two different genotypes [25
]. We made substantial efforts to contact the authors of these seven trials as well as researchers known to be active in the field of pharmacogenetics, but we did not succeed in receiving additional unpublished data. Thus, our analysis might be subject to publication bias. While publication bias is a common problem in systematic reviews, the situation might be aggravated in reviews of genetic data. Reporting of genetic data is in general poor and most "negative" results of association studies do not even reach conference proceedings [37
Despite an overall lack of evidence, some of our findings merit attention. For example, the second largest study of Caucasians with chronic nephropathies [24
] showed a consistent trend towards a beneficial effect for various surrogate and clinical outcomes, whereas II carriers appeared to be unresponsive to treatment. Comparable results have been observed in the reduction of plasma ACE activity for patients after coronary artery bypass surgery [22
]. On the other hand, the findings of the largest study [23
], including diabetic patients with normo- or microalbuminuria, yielded conflicting results to the above-discussed effect modification in Caucasians. In terms of baseline values of the main outcome (level of albumin extraction rates), differences between genotypes limit the interpretation of these results. Looking at the results of the Asian study [21
], DD carriers did not benefit from ACE inhibitor therapy while DI carriers showed moderate and II carriers showed large treatment responses. Arguably, these conflicting results for treatment success of ACE inhibitors between the genetic subgroups in Asians and Caucasians might be attributed to a different genotype-phenotype relationship. In Asians, the prevalence of the D allele frequency ranges from 27 to 40 percent, whereas in Caucasians, it ranges from 50 to 63 percent. Additional ethnic factors might also affect these genotype-phenotype relationships. For example, the level of circulating ACE is 60% higher in Caucasian DD carriers than in II carriers, whereas for Asians, there are no differences [8
From the patient and clinician's perspective, it is still too early to draw solid conclusions about the optimal treatment among different genotypes. We can, however, speculate that an effect modification exists and that pharmacogenetic testing of the I/D polymorphism might provide additional information about the adequate treatment for these patients. From the public health perspective, it remains unclear whether pharmacogenetic testing would be justifiable in clinical practice. Before investing additional resources to reevaluate our preliminary observations in a primary study of high methodological quality, it might be informative to assess whether screening patients for the I/D polymorphism would have potential economic value. One recent economic analysis showed, for example, that screening men for the I/D polymorphism before starting lipid-lowering therapy with statins would result in considerable cost savings [39
]. Thus, estimations of the potential cost-effectiveness of this pharmacogenetic test might be worth considering before starting ACE inhibitor treatment.