Abstract
Hypertension is an enormous public-health challenge in the world due to its high prevalence and consequent increased cardiovascular disease morbidity and mortality. Observational epidemiologic studies and clinical trials have demonstrated a causal relationship between sodium intake and elevated blood pressure (BP). However, BP changes in response to sodium intervention vary among individuals—a trait called sodium sensitivity. This paper aims to review the recent advances in sodium-sensitivity research in Chinese and other populations. Older age, female gender, and black race are associated with high sodium sensitivity. Both genetic and environmental factors influence BP sodium sensitivity. Physical activity and dietary potassium intake are associated with reduced sodium sensitivity while obesity, metabolic syndrome, and elevated BP are associated with increased sodium sensitivity. Familial studies have documented a moderate heritability of sodium sensitivity. Candidate gene association studies, genome-wide association studies, whole-exome, and whole-genome sequencing studies have been conducted to elucidate the genomic mechanisms of sodium sensitivity. The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, the largest family-based feeding study to date, was conducted among 1906 Han Chinese in rural northern China. This study showed that ~32.4% of Chinese adults were sodium sensitive. Additionally, several genetic variants were found to be associated with sodium sensitivity. Findings from the GenSalt Study and others indicate that sodium sensitivity is a reproducible trait and both lifestyle factors and genetic variants play a role in this complex trait. Discovering biomarkers and underlying mechanisms for sodium sensitivity will help to develop individualized intervention strategies for hypertension.
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Introduction
Hypertension is an enormous public health challenge due to its high prevalence and consequent increased cardiovascular disease and related premature death and disability worldwide [1,2,3]. Globally, the prevalence and absolute burden of hypertension increased from 25.9% and 921 million in 2000 to 31.1% and 1.39 billion in 2010 [1]. A large number of observational epidemiological studies have documented a positive and significant association between dietary sodium intake and high blood pressure (BP) [4, 5]. Randomized controlled clinical trials have provided unbiased evidence for a causal relationship between reduced dietary sodium intake and BP reduction [6, 7].
Kawasaki et al. [8] and later on Weinberger [9] were among the first to recognize the heterogeneity of BP in response to sodium intake and develop the concept of sodium sensitivity in humans. Renal sodium handling and vascular endothelium have been proposed as important mechanisms regulating sodium sensitivity of BP in humans [10]. Sodium sensitivity of BP is not only associated with hypertension but also independently associated with cardiovascular disease and mortality [11, 12]. A prospective cohort study conducted by Weinberger and colleagues used rapid sodium loading and depletion methods to identify sodium sensitivity and found that sodium sensitivity of BP is associated with mortality in both normotensive and hypertensive subjects [11]. Morimoto and colleagues carried out a retrospective study of cardiovascular events in patients with essential hypertension who had a measured sodium sensitivity by dietary sodium intake in clinic [12]. They observed that cardiovascular events occurred more frequently in patients with documented sodium sensitivity of BP.
Examining the genetic and environmental determinants of sodium sensitivity of BP has important public health and clinical implications. Establishing a relationship between genetic variants and sodium sensitivity will help identify individuals at high risk for developing hypertension whom could also benefit from a low sodium dietary intervention and/or pharmaceutical treatment with novel genotype-based drugs. In addition, identifying genes that specifically interact with dietary sodium intake on the regulation of BP will contribute significantly to our knowledge about physiological pathways underlying hypertension. Identifying genetic variants associated with sodium sensitive hypertension will also aid in the development of new antihypertensive medications that target biological pathways related to sodium metabolism. From a public health standpoint, individuals with a modifiable genetic risk of hypertension could be identified prior to disease development, and effective and appropriate lifestyle modifications or novel pharmaceutical therapies could be implemented for primary prevention. Advances in this area of medicine could significantly enhance the clinical effectiveness of patient care and population-based prevention of hypertension.
In this review paper, we aim to examine the current knowledge of sodium sensitivity in Chinese and other populations, including testing methods and reproducibility of sodium sensitivity, proportion of sodium sensitivity in populations, and genetic and lifestyle determinants of sodium sensitivity.
Definition and testing of sodium sensitivity
The definition of sodium sensitivity varied between studies. It is most often defined as a proportional change (i.e., ≥3% to ≥10%) or an absolute change (i.e., ≥3 to ≥10 mmHg) in mean arterial pressure during sodium intervention. Currently, two common methods have been used to assess sodium sensitivity of BP. The first is to measure the response of BP to low and high dietary sodium intake over 1–2 weeks. The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, which was a large family-based dietary feeding study, used this method to measure sodium sensitivity (Fig. 1) [13]. Study participants received a low-sodium diet (3 g of sodium chloride or 51.3 mmol of sodium per day) for 7 days, followed by a high-sodium diet (18 g of sodium chloride or 307.8 mmol of sodium per day) for an additional 7 days. BP and urinary sodium excretion were measured on the last 3 days of each week. In general, the dietary approach is believed to be more clinically relevant and is considered the gold standard for the characterization of sodium sensitivity.
Another method is to assess BP response to rapid sodium loading and depletion. Weinberger and colleagues using a protocol that began with the intravenous administration of 2 L normal (0.9%) saline over 4 h in the morning. BP was measured at the completion of the infusion at noon. On the following day, sodium and volume depletion were induced by a 10 mmol sodium diet and three doses of oral furosemide (40 mg every 8 h). BP was measured again in the following morning. Sodium sensitivity of BP was defined as a decrease in mean arterial pressure ≥ 10 mmHg, and salt resistance was defined as a decrease < 6 mmHg [11].
Reproducibility of sodium sensitivity
A few studies have tested the long-term reproducibility of sodium sensitivity of BP [14, 15]. Sharma et al. used mean arterial pressure response after a reduced sodium intake (from 220 to 20 mmol/day) > 3 mmHg to define sodium sensitivity. They reported the reliability of classification of sodium sensitivity by the κ statistic was 0.87, implying a strong agreement between the two responses to dietary sodium intake [14]. In the GenSalt Study, the low and high dietary sodium interventions were repeated among 487 Chinese adults 4.5 years after the original test using the identical study protocol [15]. BP responses to dietary intervention in the initial and later repeated studies were highly correlated. For example, the correlation coefficients for systolic BP levels were 0.77 at baseline, 0.79 during low-sodium, and 0.80 during high-sodium interventions (all P < 0.0001). The correlation coefficients for systolic BP changes were 0.37 from baseline to low sodium and 0.37 from low-sodium to high-sodium intervention (all P < 0.0001). These data suggest that BP responses to dietary sodium interventions have long-term reproducibility and stable characteristics in the general population [15].
Proportion of sodium sensitivity in Chinese and other populations
BP response to dietary sodium intake in human subjects is a continuous and normally distributed trait. The distribution of BP responses to low and high dietary sodium interventions from the GenSalt Study are shown in Fig. 2 [13]. These data show that BP responses to dietary sodium intake were normally distributed and no evidence for a bimodal distribution in this population was found. Both systolic BP and diastolic BP decreased during the low-sodium intervention and increased during the high-sodium intervention among majority of participants [13]. Using a cut-off to categorize subjects as sodium sensitive or sodium resistant is arbitrary. If sodium sensitivity is defined as an absolute change of 5 mm Hg or more in mean arterial pressure, 33.9% of participants during the low-sodium intervention and 32.4% during the high-sodium intervention would have met the criteria. If a proportional change of 5% or more in mean arterial pressure was as definition of sodium sensitivity, 38.7% of participants would have met the criteria during the low-salt intervention and 39.2% during the high-salt intervention [13].
The proportion of sodium sensitivity of BP among various populations is shown in Table 1. Most of these studies were conducted in hypertensive patients with a small sample size [1, 8, 16, 17]. Different study protocols were employed, e.g., dietary sodium intake increased from 9 to 249 mmol per day in some studies [8, 16] and from 70 to 345 mmol per day in others [18]. In addition, sodium sensitivity was defined as the difference in mean arterial pressure between low and high-sodium interventions ≥ 10% or ≥10 mmHg in some studies [8, 16,17,18,19,20] or ≥3% or ≥3 mmHg in others [14, 21]. Using a definition of mean arterial pressure ≥ 10% or ≥10 mmHg, the proportions of sodium sensitivity varied from 32% to 64% among individuals with hypertension and 0–50% among individuals with normal BP [19, 20].
Sodium sensitivity by age, sex, and race/ethnicity
Much epidemiological evidence suggests that the age-related increases in BP may be related to sodium sensitivity due to age-related decrease in renal sodium handling [22, 23]. Miller and colleagues found that BP response to the manipulation of dietary sodium was correlated with age being higher among those > 40 years old in normotensive adults [24]. Hurwitz and colleagues reported that every 10 years of age was associated with a 2.4 mmHg increase in sodium sensitivity of systolic BP in hypertensive patients [25]. In the GenSalt Study, systolic BP increased 4.3, 5.7, and 7.4 mmHg from low-sodium to high-sodium interventions among individuals aged <35, 35–44, and ≥45 years (P < 0.0001 for trends) [13].
The GenSalt Study and others have shown that BP responses to dietary sodium intervention were more pronounced in women than in men [13, 26, 27]. In the GenSalt Study, BP responses to high-sodium interventions were significantly greater in women than in men: 6.4 versus 5.2 mmHg for systolic and 3.1 versus 1.7 mmHg for diastolic (all P < 0.001). Physiological studies have suggested that female hormones (estrogen and progesterone) might be associated with increased renal sodium reabsorption and water retention [28, 29]. In addition, the GenSalt Study suggests that genes encoding sex hormones could have important influences on the sodium sensitivity of BP [30].
Previous studies have documented that sodium sensitivity is more common among individuals of African-American descent [20, 31]. In the DASH-sodium trials, the decrease in BP associated with reduced sodium intake was more pronounced in normotensive African Americans [31]. Wright et al. reported the prevalence of sodium sensitivity was similar in both black and white normotensives but increased in African Americans hypertensives [20]. The reason for this difference in race may be because blacks have an intrinsic reduction in the ability to excrete sodium compared with whites [32].
Determinations of sodium sensitivity
Usual BP levels
Individuals with hypertension have a greater BP response to changes in sodium intake than individuals without hypertension [9, 13, 20]. Weinberger and colleagues found that sodium sensitivity of BP was more common in hypertensive than in normotensive subjects [9]. In GenSalt Study, He and colleagues indicated that BP responses to dietary sodium intervention increased with age and higher baseline BP levels, especially for systolic BP [10]. In the GenSalt Study, systolic BP increased 4.1, 5.5, and 7.7 mm Hg from low-sodium to high-sodium intervention among individuals with baseline BP < 120/80, 120–139/80-89, and ≥140/90 mmHg (P < 0.0001 for trends) [13].
Cold pressor test
The cold pressor test, which measures the response of BP to the stimulus of external cold, has been used as a standard measure for characterizing sympathetic nervous system activity in response to stress in normotensive and hypertensive subjects and has been suggested to predict the subsequent risk of hypertension in normotensives [33,34,35]. Previous studies have also suggested that sympathetic nervous system activity might play a fundamental role in determining sodium sensitivity of BP [36]. In the GenSalt Study, a dose–response relationship between BP responses to cold pressor and dietary sodium interventions was identified [37]. Systolic BP responses by the quartiles of area-under-the-curve of response to cold pressor were −2.6, −4.6, −5.7, and −8.5 mmHg during low-sodium intervention and 4.1, 4.4, 4.4, and 6.3 mmHg during high-sodium intervention (all P < 0.001 for trends). These results indicated that BP response to cold pressor was associated with sodium sensitivity. The GenSalt follow-up study indicated that BP response to the cold pressor is a reproducible measure of cardiovascular reactivity to stress [38, 39].
Obesity
In addition to increasing the risk of hypertension, obesity has been linked to sodium sensitivity of BP [40,41,42]. Rocchini and colleagues reported that obese adolescents had a significantly larger reduction in mean arterial pressure (−12 mmHg) than non-obese adolescents (1 mmHg) after successive 2-week periods of a high-salt diet (>250 mmol of sodium per day) and a low-salt diet (<30 mmol per day) [40]. Uzu and colleagues reported that central obesity was an independent risk factor for sodium-sensitive hypertension (odds ratio, 1.41; 95% confidence interval, 1.04–1.91) [41]. In GenSalt study, waist circumference was significantly associated with greater BP responses to dietary sodium intake [42]. Abdominal obesity might be especially important in determining sodium sensitivity of BP primarily due to altered insulin resistance and renal tubular sodium handling [43].
Metabolic syndrome
Metabolic syndrome, a cluster of metabolic disorders including central obesity, insulin resistance, hyperglycemia, dyslipidemia, and elevated BP, is strongly associated with sodium sensitivity [41, 42, 44]. Hoffmann and colleagues reported that reducing dietary salt from a usual intake of 8.2 –2.3 g/day lowered systolic BP by 8.7, 6.0, 3.4, 1.1, and 1.0 mm Hg, respectively, among individuals with 4–5, 3, 2, 1, and 0 components of the metabolic syndrome (P < 0.0001) [44]. In the GenSalt Study, multivariable-adjusted mean changes (95% CIs) in BP were significantly greater (all P < 0.0001) among participants with metabolic syndrome compared to those without: 6.51 (5.76, 7.26) versus 4.55 (4.26, 4.84) for systolic BP, and 3.25 (2.56, 3.94) versus 1.69 (1.42, 1.96) for diastolic BP during the high-sodium intervention [42]. In addition, participants with 4 or 5 components of metabolic syndrome had a 3.13-fold increased odds (95% CI 1.80, 5.43) of sodium sensitivity during the high-sodium intervention. The underlying mechanism of increased sodium sensitivity in individuals with metabolic syndrome is not fully understood. Insulin resistance and concomitant compensatory hyperinsulinemia might lead to sodium retention and extracellular fluid volume expansion, thereby increasing BP responses to sodium intake [45, 46].
Physical activity
Prospective cohort studies reported that physical activity was significantly and inversely associated with the risk of hypertension [47] and randomized controlled trials documented that physical activity lowered BP in both normotensive and hypertensive individuals [48]. In the GenSalt Study, physical activity was significantly, independently, and inversely related to sodium sensitivity of BP, with a graded dose–response association between lower levels of physical activity and higher sodium sensitivity [49]. This protective effect might occur through several potential mechanisms, such as reduction of insulin resistance, improvement of endothelial function, and inhibition of sympathetic nervous system activity [46].
Potassium intake and diet
Randomized clinical trials documented that potassium intake lowers BP in both hypertensive and normotensive individuals [50]. In addition, dietary potassium intake modified BP responses to dietary sodium intake [21, 51]. Morris and colleagues tested the effects of potassium supplementation on sodium sensitivity in 38 healthy normotensive men who consumed a low sodium (15 mmol/day) and potassium (30 mmol/day) diet. Supplementing potassium up to 70 mmol/day attenuated BP response to sodium increase and abolished BP response at levels up to 120 mmol/day [21]. Coruzzi and colleagues reported that potassium depletion increased BP and sodium sensitivity [51]. In GenSalt Study, 60 mmol/day of potassium supplementation diminished BP increases due to high sodium intake [13]. Dietary potassium deficiency induced sodium sensitivity by increasing renin–angiotensin–aldosterone activity and induction of tubulointerstitial injury [52].
Heritability of sodium sensitivity
Previous family studies conducted in various populations reported that the heritability of usual BP ranged from 20% to 50% [53, 54]. Furthermore, several studies reported moderate heritability of BP sodium sensitivity [55,56,57]. Miller and colleagues studied 44 monozygotic twins and their families in a dietary sodium restriction (<75 mmol/day) intervention over a 12-week period [55]. The familial correlations for the BP responses to low-sodium as compared to baseline sodium intake were significant, and heritability of BP response was 54% for systolic and 34% for diastolic using the age-weight-adjusted residual variance. Svetkey et al. examined 20 African-American families selected through a hypertensive proband in whom sodium sensitivity was determined with an intravenous sodium-loading and furosemide volume-depletion protocol [56]. The heritability estimates based on familial correlations were 26–84% for mean arterial pressure, 26–74% for systolic, and 0.4–24% for diastolic BP responses to the sodium sensitivity maneuver, respectively [56]. In the GenSalt Study, the heritabilities for percentage of BP responses to low-sodium were 0.20, 0.21, and 0.23; and to high-sodium were 0.22, 0.33, and 0.33 for systolic, diastolic, and mean arterial pressure, respectively [57]. These findings suggest that BP responses to dietary sodium intervention are familial and genetic factors may play a moderate role in sodium sensitivity of BP.
Genetic association studies of sodium sensitivity
Candidate gene studies have provided evidence that genetic variants contribute to BP sodium sensitivity. Table 2 summarizes genetic variants related to sodium sensitivity of BP by biological pathways.
The renin–angiotensin–aldosterone system (RAAS)
Variants in several candidate genes in the RAAS pathway, including angiotensin-converting enzyme (ACE) [58,59,60], angiotensinogen (AGT) [61,62,63,64,65,66], cytochrome P450, family 11, subfamily B, polypeptide 2 (CYP11B2) [67,68,69], and others [70,71,72,73,74] have been associated with sodium sensitivity of BP.
In the GenSalt Study, the associations between 12 candidate genes in the RAAS (ACE, ACE2, CYP11B1, CYP11B2, HSD11B1, HSD11B2, AGT, AGTR1, AGTR2, REN, NR3C2, and RENBP) and sodium sensitivity of BP were examined [75, 76]. Using a stringent significant threshold, six ACE2 gene variants (rs1514283, rs1514282, rs4646176, rs2074192, rs714205, and rs2285666) were significantly associated with BP responses to low-sodium intervention. The first three of them were also significantly associated with mean arterial pressure response to high-sodium intervention. In addition, variants in AGTR1 (rs4524238 and rs3772616), HSD11B2 (rs5479), and RENBP (rs1557501 and rs2269372) were significantly associated with BP responses to low-sodium intervention in single marker analyses and haplotype analyses.
Ion and water channels, transporters, and exchangers
Ion and water channels, transporters, and exchangers are actively involved in the regulation of sodium balance, blood volume, and BP. The renal epithelial sodium channel (ENaC) mediates sodium reabsorption in the renal tubule and plays a key role in sodium sensitivity of BP [77, 78]. A number of variants encoding ENaC subunits and other channels, transporters, and exchangers were identified as being related to sodium sensitivity of BP [79,80,81,82,83,84,85,86].
In the GenSalt Study, associations between genetic variants in ENaC and sodium sensitivity of BP were explored [87,88,89]. Several variants in SCNN1G were significantly associated with BP response to a low-sodium intervention, including rs4073930, rs4073291, rs7404408, rs5735, rs4299163, and rs4499238. In addition, SGK1 polymorphism rs2758151 was significantly associated with diastolic BP response to a high-sodium intervention. Furthermore, SLC4A4 marker rs4254735 was significantly associated with diastolic BP response to a low-sodium intervention and rs10022637 was associated with systolic and diastolic BP responses to a high-sodium intervention.
In addition, two other studies reported that one SLC8A1 SNP (rs434082) and three WNK1 SNPs (rs880054, rs12828016, and rs2301880) were associated with sodium sensitivity in the Chinese population [90, 91].
Endothelial system
Endothelial dysfunction, especially the nitric oxide system, is involved in both hypertension and sodium sensitivity of BP [92]. Human studies have indicated that the increase in BP during sodium interventions was associated with the T-786C polymorphism of nitric oxide synthase gene [93, 94]. Polymorphisms of other genes that play important roles in the pathogenesis of BP sodium sensitivity were also identified [95,96,97,98,99].
The GenSalt Study carefully examined 14 candidate genes in the endothelial system and 11 NADPH oxidase-related genes [100, 101]. Variants in DDAH1, COL18A1, VWF, and RAC1 genes were associated with BP sodium sensitivity. Interestingly enough, 10 variants from SELE displayed significant genotype–sex interactions, with eight of them only significant in men.
Intracellular messengers
Both the guanine nucleotide-binding protein β-polypeptide 3 (GNB3) and a-adducin (ADD1) genes have been indicated in BP sodium sensitivity due to their biological effects on sodium homeostasis via sodium–proton exchanger activity and renal tubular sodium reabsorption, respectively [102,103,104,105,106,107,108,109,110,111]. Many reports have investigated the association between the GNB3 C825T and ADD1 Gly460Trp polymorphisms and BP responses to sodium intervention. Although there is little evidence for a role of the GNB3 C825T variant in sodium sensitivity, many studies have identified increased sodium sensitivity among those with the ADD1 460Trp allele compared to those with the 460Gly allele [104,105,106,107,108,109,110,111].
GenSalt investigators carefully genotyped variants covering the GNB3 and ADD1 genes [112]. Non-significant associations were found regarding GNB3 C825T polymorphism and the ADD1 Gly460Trp polymorphism. Despite these negative results, a rare ADD1 mutation, rs17833172, was identified to influence BP response to sodium interventions. Another novel finding is that participants carrying the A allele of SNP rs1129649 of the GNB3 gene had a significantly decreased mean arterial pressure response to low-sodium intervention.
Sympathetic nervous system
One of the main mechanisms by which the sympathetic nervous system exerts its influence on BP is through its interaction with the kidney and the RAAS. Studies have demonstrated that increased renal sympathetic nerve activity results in renal vasoconstriction with decreased glomerular filtration rate and renal blood flow, increased renal vascular resistance, increased renal tubular reabsorption of sodium and water, and increased renal release of renin and norepinephrine [113, 114]. Several studies demonstrate that the genes encoding the G-protein-coupled receptor kinase type 4 (GRK4) and β-2 adrenergic receptor (ADRB2) are strong candidates for sodium sensitivity [63, 115,116,117]. One of the ADRB2 variants, rs1042714, was successfully replicated in an independent Chinese population by Liu et al. [90].
GNAI2 polymorphisms were found to be associated with hypertension risk in the Millennium Genome Project [118]. GenSalt investigators provided the first evidence that a GNAI2 SNP (rs10510755) was positively associated with sodium sensitivity of BP [119]. Further exploration of genes in this pathway could yield new insights into this trait.
Apelin-APJ system
The apelin system, including apelin and its G-protein coupled-receptor APJ, is a peptide signaling pathway that is implicated in the regulation of cardiovascular function and fluid homeostasis. This system is implicated in the regulation of BP via a NO/cGMP-dependent mechanism and can influence the Ca2+ transient in cardiomyocytes [120]. Mutations of the apelin and APJ genes have recently been reported to be associated with hypertension [121]. SNPs rs2282623 and rs746886 in the apelin and APJ genes were significantly associated with diastolic BP and mean arterial pressure responses to low-sodium intervention in the GenSalt Study population [76].
The natriuretic peptide (NPP) system
Studies have demonstrated a role for the NPP system in the stimulation of diuresis and natriuresis via direct inhibition of sodium reabsorption in the medullary collecting duct, alteration of renal hemodynamics, and inhibition of renin and aldosterone activity [122]. Widecka et al. first identified an association between an atrial NPP (NPPA) variant and sodium sensitivity of BP [123]. In addition, Citterio et al. detected three SNPs in PRKG1 gene (rs1904694, rs7905063, and rs7897633) that were associated with BP change after acute salt load [81].
The GenSalt study successfully replicated the NPPA variant, rs5063, in the Chinese population and a novel NPPC variant, rs2077386, was also identified [124]. In addition, the chromosomal region 2p24.3-2p24.1 was linked to BP responses to a high-sodium intervention [125]. The SNP rs16983422, upstream from VSNL1 in the linkage region, had a marginally significant association with diastolic BP and mean arterial pressure responses to a high-sodium intervention.
The kallikrein–kinin system
Kinins are small peptides which are produced from kallikrein and cause vasodilation, diuresis, and natriuresis. The GenSalt Study systematically examined the associations of the 11 genes in KKS system (KNG1, KLK1, KLKB1, BDKRB1, BDKRB2, SERPINA4, CPN1, CPN2, CPM, ECE1, and MME) and sodium sensitivity of BP [126]. The BDKRB2 variant, rs11847625, was significantly linked with sodium sensitivity and the carrying minor C allele could attribute to increased systolic BP response. Seven ECE1 variants showed significant associations with increased diastolic BP response to low-sodium intervention. These seven SNPs were highly correlated with each other and haplotype analysis revealed a similar relationship.
Variants in other biological candidate genes have also been reported to associate with sodium sensitivity of BP (Table 2) [96, 98, 127,128,129,130,131,132,133,134,135].
Genome-wide association studies of sodium sensitivity
Genome-wide association study (GWAS) represents a powerful tool for investigating the common genetic variants associated with complex diseases. The GenSalt Study published the only GWAS findings on BP sodium sensitivity phenotypes and identified four novel loci for which physically mapped in or near PRMT6 (rs1330225), CDCA7 (rs10930597), PIBF1 (rs8002688), and IRAK1BP1 (rs16890334) [136]. The most significant SNP from each of the first two loci is located in the intergenic regions. The PIBF1 gene encodes a progesterone-induced molecule known to interact with leptin to mediate the effects of progesterone during pregnancy and the putative role of this gene in BP regulation is unclear. IRAK1BP1 is part of the signaling pathway that leads to activation of nuclear factor-κ-B1 [137]. A transcription factor for pro-inflammatory pathway genes, inhibition of nuclear factor-κB, has been shown to decrease inflammation, BP, and angiotensin-II-induced target end-organ damage in animal models [138], representing a plausible biological mechanism underlying the observed association. In addition, the nearby gene PHIP has been shown to modulate insulin signaling, whereas HMGN3 represents an important regulator of glucose-stimulated insulin secretion [136].
Sequencing studies of sodium sensitivity
With the ability to directly identify causal variants and rare mutations, next-generation sequencing is becoming the primary discovery tool in genomic research [139]. In the GenSalt Study, seven RAAS genes were re-sequenced using capillary-based sequencing methods [140]. Aggregate rare variant analysis revealed an association of the RAAS pathway with BP sodium sensitivity. Carriers of rare RAAS variants had a 1.55-fold higher odds of sodium sensitivity compared to non-carriers (P = 0.004). In addition, the APLN gene was significantly associated with sodium sensitivity, with rare APLN variants conferring a 2.22-fold higher odds of sodium sensitivity (P = 0.03). Furthermore, a low-frequency, missense RENBP variant (rs78377269) was identified and each minor allele conferred a 2.21-fold increased odds of sodium sensitivity (P = 0.03) [140].
The GenSalt Study also re-sequenced three ENaC genes (SCNN1A, SCNN1B, and SCNN1G) [141]. Carriers of SCNN1A rare variants had a 0.52 decreased odds of BP sodium sensitivity compared with non-carriers. In single-marker analyses, three independent common variants in SCNN1A, rs11614164, rs4764586, and rs3741914 were associated with sodium sensitivity (P = 4.4 × 10−4, 1.1 × 10−8, and 1.3 × 10−3). Each copy of the minor allele of rs4764586 was associated with a 1.36-fold increased odds of sodium sensitivity, whereas each copy of the minor allele of rs11614164 and rs3741914 was associated with 0.68-fold and 0.69-fold decreased odds of sodium sensitivity, respectively [141].
Conclusion
Sodium sensitivity of BP is a common and reproducible phenotype which is not only associated with hypertension but also independently associated with cardiovascular disease and mortality. Age, gender, race/ethnicity, and baseline BP levels are important determinants of sodium sensitivity. Lifestyle (diet, alcohol, and physical activity) and genetic factors play important roles in determining individuals’ sensitivity to sodium intake. Many genetic variants associated with sodium sensitivity of BP have been identified and contribute to understanding the etiology of hypertension. Despite remarkable progress, many questions related to sodium sensitivity of BP remain unclear. Future studies are warranted to better characterize sodium sensitivity in populations and to identify novel biological pathways and genetic determinants for sodium sensitivity. A better understanding of the genetic and environmental determinants of sodium sensitivity will help identify individuals at high risk for hypertension and who should receive a low sodium dietary intervention. In addition, identifying genes that interact significantly with dietary sodium intake on the regulation of BP will greatly contribute to the knowledge and underlying mechanisms of hypertension and help develop novel treatment for elevated BP.
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Acknowledgements
Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM109036. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. YL is supported by a research training grant (D43TW009107) from the National Institutes of Health John E. Fogarty International Center, Bethesda, Maryland.
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Liu, Y., Shi, M., Dolan, J. et al. Sodium sensitivity of blood pressure in Chinese populations. J Hum Hypertens 34, 94–107 (2020). https://doi.org/10.1038/s41371-018-0152-0
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DOI: https://doi.org/10.1038/s41371-018-0152-0
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