Genes, circadian clock and nocturnal blood pressure

Blood pressure (BP) exhibits clear day–night variability, and 24-h ambulatory blood pressure monitoring (ABPM) is the most commonly used method to examine this biological rhythm. In contrast to conventional office readings or home-based monitoring, ABPM provides measurement of nocturnal BP. Under physiological conditions, the nocturnal BP is significantly lower than daytime BP, most likely as a result of reduced sympathetic drive (secondary to a downward shift of the baroreflex threshold) [1] and changes in renal excretion of sodium [2]. Additional sleep–wake rhythm-related hormonal fluctuations [3], along with psychological [4], social [4] and clinical [3] factors, further modulate nocturnal BP and determine the ultimate difference between the daytime and night-time values. The accumulated body of evidence suggests that compared with office or daytime values, nocturnal BP is a more powerful predictor of cardiovascular mortality, at least in populations with moderate-to-high cardiovascular risk. In the Dublin Outcome Study [5] night-time BP showed a stronger predictive value of cardiovascular death in hypertensive patients than the office, 24-h mean and daytime BP. In fact, nocturnal BP retained its significance as a predictor of 5-year cardiovascular mortality even after taking daytime BP into account [5]. The recent meta-analysis of more than 3000 European hypertensive patients recruited into four prospective studies confirmed that nocturnal BP was superior to daytime values in prediction of cardiovascular death [6]. It is also becoming increasingly clear that the clinical significance of nocturnal BP may extend to the general population; in a prospective observation of Italian individuals, night-time BP was a stronger predictor of mortality than the daytime BP [7]. Apart from absolute values of nocturnal BP, it is the day–night difference that shows a particularly strong and consistent association with cardiovascular morbidity and mortality. Decreased nocturnal BP reduction (or nondipping, lack of BP drop during sleep) is almost as common as dipping [8] and has been associated with the risk of target organ damage, including leukoaraiosis [9], structural renal injury [10], left ventricular hypertrophy [11] and overall cardiovascular mortality [12] in high-risk populations such as hypertensive and diabetic patients. The risk of cardiovascular events is particularly increased amongst those whose BP rises at night above the values recorded during the daytime (reverse dippers) [13]. Perhaps paradoxically, patients with an excessive decrease in nocturnal BP (extreme dippers) are also at augmented risk of cardiovascular events such as silent cerebral ischaemia [14]. The role of genetic factors in regulation of the circadian BP rhythm has not been extensively investigated. However, the results of the few studies that examined heritability of ABPM have confirmed an apparent additive genetic component of both daytime and nocturnal BP and suggested that genes may have a particularly strong effect on night-time BP. Specifically, data from African–American siblings [15], Swedish families [16] and possibly Flemish twins [17] (but not from families of east African origin [18]) have shown that heritability of nocturnal BP is higher than that of daytime readings. However, up to now, it has not been clear to what extent the daytime and night-time BPs may share the same genetic background. The study by Wang et al. [19] published in this issue of the journal provides valuable new information on the genetic architecture of circadian variation in BP. Using statistical modelling Wang et al. [19] calculated heritability estimates of 24-h ABPM phenotypes in 240 European American and 190 African–American twins. Their analysis revealed that the magnitude of daytime and night-time BP heritability was comparable across the strata of different ethnicity and zygosity. The similar heritability estimates clearly indicate that both ABPM phenotypes may be equally informative and possibly superior to office readings in genetic association studies. Most interestingly, the results of this twin study [19] also suggest that approximately 30–40% of the additive genetic effects on BP may differ between nocturnal and daytime measurements and that BP dipping pattern is likely under a strong genetic regulation [19]. Although the study is not based upon direct DNA analysis but mathematical partitioning of BP variance into genetic and environmental components, it lends important support to the hypothesis that genetic control of BP differs during the day and night. Genetic mechanisms of circadian BP rhythm have not been identified yet. Intuitively, the causative genes should map to cardiovascular regulatory systems that exhibit periodic activity during day and night. Molecules and pathways with circadian patterns coherent with that of BP are the strongest candidates for genetic studies of nocturnal BP. A good example of such a candidate molecule is renal epithelial sodium channel (ENaC), one of the major regulators of sodium homeostasis. Indeed, oscillations in expression of aldosterone-responsive alpha subunit of ENaC within the distal nephron are regulated by circadian clock [20]. Experimental knockout of clock genes leads to a disruption in the expression profile of ENaC within the kidney [20]. Whether this molecular mechanism, recently identified in rodents, could be relevant in regulation of human day–night BP rhythm and nocturnal hypertension is not clear. However, mutations in genes of ENaC subunits are well recognized as primary molecular defects underlying monogenic forms of hypertension/hypotension [21,22]. Furthermore, family-based analysis has identified a suggestive association between common variants within one of the ENaC subunit genes and nocturnal (but not daytime) BP [22]. Taken together, these data suggest that ENaC genes (SCNN1A, SCNN1B and SCNN1G) are promising candidates in the search for genetic determinants of circadian BP variation. The findings of Wang et al. [19] provide a rationale for investigating genetic mechanisms that selectively affect BP at different times of the day. Elucidation of genetic regulators of circadian BP rhythm may uncover novel mechanisms of cardiovascular regulation and illuminate new targets for pharmacological interventions specifically tailored to patients with nocturnal hypertension or those with an inadequate overnight BP dip. Acknowledgement There are no conflicts of interest.