Are the new single nucleotide polymorphisms (SNPs) relevant for hypertensive populations?

In the last decade great progress has been made in human genetics. An enormous number of single nucleotide polymorphisms (SNPs) have been identified. However, the impact of these genetic polymorphisms on the understanding of polygenic multifactorial cardiovascular disease like hypertension has yielded contrasting results [1]. In this issue of the journal, Fuchs et al. [2] describes two new SNPs located in the regulatory region of the renin (REN) gene. The authors investigated human renin promoter activity from 70 genomic DNA of healthy subjects. Two new SNPs were identified at position –5434 and –5312, with quite high allele frequency. Authors described the influence of these SNPs on the transcriptional activity of the renin gene. The SNP at position –5434 did not affect enhancer activity, on the contrary the SNP at position –5312 affected this activity by a factor of 1.8 or 1.3. The methodology used to detect both gene polymorphisms and the influence of these on REN gene transcription is very accurate, well described, and precisely discussed. As indicated by the authors, this is the first report of a direct effect of a polymorphism in the human REN genes on the level of transcription of this gene in vitro, and therefore the finding is of the greatest interest The relevance of these new SNPs for the whole hypertensive population, however, is unclear. In fact the author did not test these two polymorphisms in hypertensive populations or subgroups of hypertensive patients. The problem is not just to test a given polymorphism in a case–control study, or in familial design, but to determine the relevance of the regulatory transcriptional activity of the REN gene with the appropriate assessment of all the confounding factors. The key question is what is the most appropriate experimental and clinical setting to test the impact that these SNPs affecting renin gene transcription may have on blood pressure. To answer this question, we may consider the old controversy regarding the role of plasma renin in the regulation of blood pressure. The positions of this controversy ranged from a negative one, because plasma renin could be very high in clinical conditions associated with low blood pressure (cirrosis, nephrotic syndrome, cardiac failure), to a positive one based on the direct relation between plasma renin and the level of blood pressure after acute renal ischemia. Subsequently, this issue has been further complicated by the findings that changes in plasma renin and tissue renin do not go in parallel [3], and the status of body sodium is crucial for the pressor activity of renin [3]. Therefore any assessment of the SNP should take into account all these confounding factors. For instance, it has been shown [4] that the pressor, renal hemodynamic and aldosterone responses to angiotensin I infusion are enhanced in patients carrying the DD ACE genotype as compared to carriers of the II genotypes, only with liberal but not with low sodium intake. These findings, probably due to an overriding influence of the activation of the RAS at a low salt diet, further support the importance of considering body sodium when assessing the effect of RAS genes on blood pressure. The results on alpha-adducin polymorphisms (ADD1) demonstrated the need to take into account within the genetic and environmental context used to collect them. After the first positive findings [5], inconsistent results were obtained across populations [6]. This inconsistency may be explained, at least in part, by differences in evolutionary history or environmental conditions between populations or stratification admixture within populations and heterogeneity of pathophysiological hypertensive mechanisms. Many recent observations, in which these factors were taken into consideration, support the notion that the ADD1 polymorphisms taken alone or in combination with other gene polymorphisms are associated to hypertension or to phenotypes relevant to hypertension development. In fact, we have recently tested the interaction between ADD1, angiotensin-converting enzyme (ACE), and aldosterone synthase genes (CYP11B2), all genes modulating tubular Na re-absorption. These studies were carried out either in an acute setting [7] (blood pressure response to an intravenous infusion of Na) or in a chronic setting [8] (development of hypertension in a follow-up population study). The ACE genotypes did not have per se any influence in blood pressure to saline infusion. However, when patients with the three ACE genotypes were further divided according to ADD1 polymorphisms, a linear increase in blood pressure with the number of D allele of ACE was observed in patients with the 460Trp ADD1 allele, while the opposite trend between blood pressure and the D allele was found in carriers of the 460Gly ADD1 allele. In the longitudinal study [8] on the development of hypertension in a Belgian population (chronic setting), carriers of the ACE DD genotype displayed a slightly higher incidence of hypertension (+31%) compared to ID and II patients. This small difference was greatly magnified (+250%) when ADD1 and CYP11B2 were taken into account. These two last gene polymorphisms did not per se have any effect on the development of hypertension. However, their effect is again disclosed through the interaction with ACE polymorphism. This is due to the fact the alpha-adducin 460Trp allele enhances the effects of the ACE DD genotype, and depresses the effect of II ACE genotypes, as clearly demonstrated for: (i) the pressure natriuresis curve [7], (ii) the femoral arterial thickness [9] and (iii) the progression of renal failure [10]. Recently, more consistent data were obtained in low renin hypertensives [11–14], for the risk of coronary heart disease, or stroke [15,16]. These findings clearly indicate that the impact of a given genetic variant (i.e. adducin, renin) on blood pressure level should be evaluated within the context of the appropriate environmental and genetic epistatic interactions. A negative finding or a minor genetic effect in a general population may become a major gene effect in a subset of people with the appropriate genetic and environmental backgrounds. As for the adducin paradigm, the authors describing the two new renin gene polymorphisms in the current issue of the Journal of Hypertension [2], should examine the allele frequency of the two SNPs in the hypertensive population, and should test these polymorphisms in a well-characterized set of hypertensive patients, as, for example, those with low renin hypertension, in order to better clarify the role of the given SNPs in the regulatory region of the REN gene. To conclude, any study aimed at evaluating the role of a SNP on a given gene must take into account all the appropriate genetic and environmental interaction that may modulate the effects of the proteins involved by the gene variant of interest.