Genetic determinants of blood pressure reduction following potassium supplementation: and the candidates are… (2010)

Hypertension, elevated blood pressure (BP), is a very prevalent condition that affects 25% of adults worldwide [1]. Hypertension is a major public health concern, as BP is a strong risk factor for coronary heart disease, stroke, heart failure and chronic renal diseases [2–4]. Hypertension results from both environmental and genetic factors. Dietary factors play a major role in the development of high BP, and high sodium consumption, in particular, is a major contributor to the risk of hypertension and its consequences. Convincing epidemiological data have established that individuals and societies consuming high amounts of sodium have higher mean BPs and a higher prevalence of hypertension [5–7]. It follows that sodium consumption could also be an important modulator of the genetic predispositions to hypertension. Dietary measures can also serve as important therapeutic interventions to reduce BP [8]. Clinical studies [9–11] have demonstrated that low-sodium diets as well as diets that promote the consumption of fruits, vegetables and low-fat dairy products and reduced saturated fat and cholesterol can significantly reduce BP. High amounts of dietary potassium are believed to contribute to reductions in BP [8]. Previous data suggest that the BP-lowering effects of potassium are more apparent in a context of high sodium intake [12]. Unfortunately, these dietary measures are difficult for patients to comply with in the long term, and the supplementation of key nutritional elements from these diets has been suggested as potentially helpful to reduce BP or the risk of cardiovascular diseases. For example, the cardiovascular benefits of omega-3 polyunsaturated fatty acid supplements have been highlighted in clinical trials [13,14]. Of particular interest is the potential benefit of dietary supplementation of potassium. Epidemiological studies have associated a high consumption of potassium with lower BP [6], and a previous meta-analysis [12] has suggested that potassium supplementation results in significant reductions in BP. In the absence of direct evidence from large randomized controlled trials demonstrating reductions of cardiovascular events with potassium supplements, current guidelines do not endorse the use of such supplements but rather promote a diet of foods rich in potassium such as fruits and vegetables [8]. The mechanisms responsible for these BP reductions are complex and remain to be fully elucidated [15]. Interestingly, a significant interindividual variability is apparent in the BP reductions that are induced by potassium supplementation [12,16]. Because a moderate heritability exists to these effects [17], it can be anticipated that genetic variations could be useful in explaining part of this variability and, perhaps, to identify individuals who are most likely to benefit from potassium supplementation or targeted dietary interventions. In this issue of the Journal of Hypertension, Montasser et al. [18] present the results of a candidate gene substudy from the Genetic Epidemiology Network of Salt Sensitivity (GenSalt). GenSalt is a large dietary study aiming the identification of genes involved in the BP response to dietary sodium and potassium interventions in a well phenotyped cohort of individuals from six rural villages in northern China [19]. Previous GenSalt publications have had a tremendous impact on our understanding of the heritability of BP response to dietary sodium and potassium supplementation [17], the correlation between the responses to these dietary interventions [20], and have highlighted possible modulators of these dietary interventions [16,21]. In their current substudy, the GenSalt investigators looked at the association between 23 single-nucleotide polymorphisms (SNPs) from three genes (NOS3, the nitric oxide synthase 3 coding gene; EDN1, the endothelin 1 coding gene and SELE, the E-selectin coding gene) and the BP-lowering effects of a 60 mmol potassium supplement in 1843 of the 1906 participants who took part in the dietary intervention phase of GenSalt. While receiving this potassium supplement, all the patients were maintained on a high-salt diet of 18 g per day (307.8 mmol/day of sodium). The results from this investigation suggest that four SNPs in the EDN1 gene are associated with BP response to potassium supplementation and that a gene-by-gene interaction may be present between EDN1 and SELE, although none of the SNPs in the latter gene were independently associated with BP reductions in the main effects analysis. Before we go on, it may be helpful to pause to describe the general procedure of a candidate gene association study. Candidate gene studies aim to identify genetic variants that are associated with the development of a disease or response to a therapeutic intervention, but does so by limiting the search to genetic variants from a set of preselected genes that are chosen based on the current state of scientific knowledge and what is known or suspected about the biological mechanisms of those genes with respect to the phenotype under study. Common and rare genetic variations and mutations within and near the coding regions of the selected candidate genes are then genotyped and tested for association. In pharmacogenomic studies, for example, genes encoding proteins implicated in the pharmacokinetics or pharmacodynamics of a drug under study would typically be selected. This approach is in marked contrast with genome-wide association studies, in which one would test a very large number of unselected anonymous common genetic variants covering the entire genome more or less uniformly. Both of these complementary strategies have potential advantages and limitations [22,23]. As the biological and physiological mechanisms underlying BP reductions produced by potassium supplementation are extremely complex, designing a candidate gene study to this end is not so straightforward. NOS3 is a reasonable candidate [24], and extensive data have implicated EDN1 in the physiopathology of hypertension and salt sensitivity [25], but its implication in the BP-lowering effects of potassium remains uncertain [26]. SELE, on the contrary, is a much less obvious candidate, especially when compared, for example, with genes related to the renin–angiotensin–aldosterone system, adrenergic system or sodium and potassium channels, pumps or transporters [26]. The GenSalt investigators have previously reported evidence for a moderate association between the BP response to potassium supplementation and the high-sodium diet [20], as well as to the cold pressor test [27], making a strong case in favor of genetic variants involved in salt sensitivity and the adrenergic system. But what's more, the genetic community has had relatively limited and delayed success in its search of genetic determinants of hypertension. It is only recently that well powered studies [28–30] were able to identify and replicate association between genetic variants and BP, and SELE, NOS3 or EDN1 do not come out as important modulators of BP in those studies. Nonetheless, these genes could still make a modest polygenic contribution to hypertension, particularly given the extensive data supporting the implication of endothelin 1 and nitric oxide in BP and vascular regulation. The absence of functional studies and the limited data supporting the genetic association with hypertension or the physiology of BP modulation by potassium greatly limits discussion of the potential mechanisms underlying the associations, as rightfully underscored by Montasser et al. [18]. These limitations also impact the conclusions that can be reached from the gene–gene interaction reported by the authors between SELE rs932307 and EDN1 rs1630736. In light of the fact that only 2.3% of the patients had the EDN1 rs1630736 CC–SELE rs932307–GG combination and that no association was observed in the main effect analysis for the SELE SNPs, replication in an independent study will be necessary to add support to the finding. Another point deserving attention is the possible interaction between potassium supplementation and sodium consumption. Indeed, previous reports have indicated that BP reductions following potassium supplementation are more important in patients with high sodium consumption. In the GenSalt study, patients were placed on a very high-salt diet of 18 g per day (7.1 g or 307.8 mmol/day of sodium), an amount of salt considerably higher than the average 3.4 g of sodium consumed daily by individuals in the United States [31]. Given the existing evidence that sodium consumption can significantly alter genotype–phenotype associations [32], these results may not be so readily generalizable to the normal population. The study of Montasser et al. [18] is certainly thought provoking. Despite the limitations highlighted here, the findings do offer valuable potential. Should those results be validated in a subsequent study, they could have a significant impact on our understanding of potassium physiology and perhaps contribute to the identification of individuals more likely to benefit from potassium supplementation. There remains to this day, considerable uncertainty with respect to the mechanisms underlying the potassium-induced BP reductions as well as those of dietary sodium and cold pressor on BP. The large sample size and value of the finely phenotyped GenSalt cohort make it an excellent resource for a genome-wide association study. It is hoped that the GenSalt investigators will consider using this complementary approach, which could also lead to important genetic discoveries. Acknowledgements S.deD. is the recipient of a Personnel Award from the Heart and Stroke Foundation of Canada. M.-P.D. is supported by the Fonds de la recherché en santé du Québec. There are no conflicts of interest.