Individualised therapy of angiotensin converting enzyme (ACE) inhibitors in stable coronary artery disease: overview of the primary results of the PERindopril GENEtic association (PERGENE) study

In unadjusted analysis, 7 single nucleotide polymorphisms in 4 different candidate genes were significantly associated with the treatment effect of perindopril. In multivariate permutation analysis, 3 of these SNPs, located in the AT1 receptor and BK1 receptor genes, remained significant modifiers of the treatment benefit of perindopril [26].

In the BK1 receptor gene, rs12050217 was a strong modifier of the treatment benefit of perindopril as presented in Fig. 4. Additionally, in the AT1 receptor gene, rs275651 and rs5182 significantly modified the treatment benefit of perindopril. Genetic determinants of treatment benefit of perindopril have not been demonstrated previously [26].

We constructed a pharmacogenetic risk score by combining the unfavourable alleles of the treatment effect modifying SNPs (Fig. 5) [26]. Unfavourable alleles were associated with diminished treatment effect as observed in the overall study group. The pharmacogenetic risk score demonstrated a decrease in the level of treatment benefit of perindopril with an increasing number of unfavourable alleles. In patients with no unfavourable alleles, a much more pronounced treatment benefit was observed as compared with the overall study result (which yielded a 20% relative risk reduction). By combining pharmacogenetic risk scores, we observed that the treatment benefit was concentrated in about 3 out of 4 of the patients and absent in 1 out of 4 of the patients [26]. This is the first time that subgroups of responders and non-responders to ACE inhibitor treatment have been identified. An interaction effect of similar direction and magnitude was observed in an initial confirmatory analysis of 1051 patients with cerebrovascular disease from the PROGRESS trial [26].

In the patients who were identified as responders and non-responders with pharmacogenetic profiling, no differences in clinical characteristics were observed in PERGENE [26]. Also intermediate phenotypes such as blood pressure and blood pressure reduction levels were comparable between responders and non-responders [26]. Thus, the observed treatment interaction cannot be explained by clinical differences between the genotypes but can only be prescribed to the net genetic difference between patients.

As hypertension is a strong intermediate phenotype of CAD, we investigated whether genetic variations in the cascade of RAAS/bradykinin system genes are involved in blood pressure and whether such genetic variations determine the BP response to ACE inhibitor therapy which is highly variable between patients [27]. A differential BP effect determined by genetic factors may give insight into their clinical effects.

The PERGENE study demonstrated that the genetic variants in the ACE, angiotensinogen and prorenin gene were important determinants of hypertension at baseline. These genetic determinants of hypertension in the RAAS system were also observed in the two replication cohorts of the PROGRESS trial (patients with cerebrovascular disease) and ERGO study (relatively healthy elderly subjects) [27] (Fig. 6). However, the blood pressure response to the ACE inhibitor perindopril was not modified by the genetic polymorphisms in the RAAS or bradykinin pathway.

These findings are consistent with prior subgroup analyses on blood pressure and BP reduction by ACE inhibitor therapy demonstrating that the clinical benefits are independent of blood pressure and the amount of BP reduction [20, 28, 29].

To strengthen our results, the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) consortium studied the blood pressure dependent and independent effects of ACE inhibitors in 146,838 patients and confirmed that a beneficial effect up and above blood pressure reduction is present [29]. Substudies of EUROPA have investigated the additional effects of ACE inhibitors and have established that ACE inhibitors have additional effects beyond the blood pressure reduction alone, such as the improvement of endothelial function, improvement of the neurohumoral balance, and reduction of unfavourable remodelling of the coronary arteries [30, 31].

In summary, the PERGENE study identified new genetic determinants of clinical treatment benefit of ACE inhibitors, but these genetic determinants do not mediate these effects through change in BP as these SNPs did not pop up in the analysis on BP reduction [26, 27]. The treatment effect modifying SNPs was particularly located in the AT1 and BK1 receptors. The SNPs in the AT1 receptor were located in the promoter (rs275651) and exon 4 (rs5182) on chromosome 3, the SNP in the BK1 receptor gene on chromosome 14 was located in an intron region. All three SNPs were important tagging SNPs within their candidate gene [26]. Functionality of these SNPs is at this moment unknown, but more basic research has been started based on these findings. As the AT1 receptor is involved in the direct effects of angiotensin II, it can be hypothesised that genetic variants in the AT1 receptor will influence the response to an ACE inhibitor. The exact role of the BK1 receptor, on the other hand, is less well established. Bradykinin is a potent vasodilator that also induces antiatherosclerotic and antithrombotic effects, which are mediated by BK2 receptors. Previous studies indicated that the clinical benefit of ACE inhibitors depends, at least in part, on BK2 receptor activation [32]. In the past year, more data are emerging on the effect of the BK1 receptor, the effects of which are less well known. BK1 receptors are weakly expressed under physiological conditions, but are strongly induced in response to pathological conditions and/or RAAS blockade [33, 34]. Recent reports indicate that BK1 receptor deficiency predisposes to atherosclerosis [35] and kinins and the BK1 receptor plays an important deleterious role in this process [36]. Interestingly, it has been suggested that BK1 receptors are directly activated by ACE inhibitors (thus resulting in an increase in endothelial NO release, for instance in the heart [37, 38], by which they do contribute to the cardioprotective beneficial effects of ACE inhibitors, but this has not been uniformly confirmed by others [39]. Therefore, a more likely possibility is that the upregulated BK1 receptors are activated by their endogenous ligand during ACE inhibition. Such activation results in the hypotensive [40], cardioprotective [37] and cerebroprotective [41] effects of kinins, as observed in animals, and one could speculate that patients with genetic defects in their BK1 receptor display a diminished response to ACE inhibition with regard to kinins. Indeed, in our study we observed that especially patients with the minor allele variants of the BK1 receptor were relatively insensitive or resistant to the beneficial effect of the ACE inhibitor. Clearly, more work is needed to support this interesting concept.

Still, the lack of a blood pressure related effect of the 3 identified SNPs in the treatment effect analysis suggests a different pathway of clinical effect [26, 27] and emphasises more on the bradykinin effects of ACE inhibitors as the blood pressure independent effects of ACE inhibitors is often proposed for the BK pathway [11]. Our analyses may indicate that the up-regulated BK1 receptor in stressed CAD patients may play an important role in the assumed pleiotropic effect of ACE inhibitors. Our findings do support that concept, as it might be speculated that the genetic defects in the BK1 receptor alter the antiatherosclerotic properties of the ACE inhibitor treatment effect which might be an important cornerstone of the treatment benefit besides blood pressure lowering.