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BACKGROUND To explore how central hemodynamics respond to dietary sodium and potassium interventions, and whether the responses are associated with metabolic traits. METHODS We conducted a dietary intervention study including a 7-day low-sodium (51.3 mmol sodium/day) intervention, a 7-day high-sodium (307.8 mmol sodium/day) intervention, and a 7-day high-sodium with potassium supplementation (60.0 mmol potassium/day) intervention among 99 northern Chinese subjects aged 18–60 years. Five metabolic traits included abdominal obesity, high triglycerides, low HDL cholesterol, raised blood pressure (BP), and high glucose. Central hemodynamics were measured at baseline and during each intervention. RESULTS Central systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), and augmentation index (AIx@75) significantly decreased during low-sodium intervention, increased during high-sodium intervention, and then decreased during potassium supplementation. We observed potential linear trends toward significance of central SBP and PP responses to low-sodium intervention, and significant linear trends of responses to high-sodium intervention as the number of metabolic traits grows. For example, among participants with 0 or 1, 2 or 3, and 4 or 5 metabolic traits, central SBP responses to high-sodium intervention were 8.8 [95% confidence interval (5.8, 11.8)], 9.3 (7.1, 11.6), and 14.0 (11.6, 16.3) mmHg, respectively (P for trend = 0.009). Significant linear trends of central SBP and DBP responses to potassium supplementation were also observed. CONCLUSIONS Central BP and AIx@75 were lowered by sodium reduction and potassium supplementation, and elevated by sodium-loading. The responses of central BP were pronounced among individuals with metabolic traits clustering. CLINICAL TRIALS REGISTRATION Trial Number NCT00721721 (The current study is registered on ClinicalTrials.gov; https://clinicaltrials.gov).

BACKGROUND The aim of this study was to comprehensively test the associations of genetic variants of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-related genes with blood pressure (BP) responses to dietary sodium intervention in a Chinese population. METHODS We conducted a 7-day low-sodium intervention followed by a 7-day high-sodium intervention among 1,906 participants in rural China. BP measurements were obtained at baseline and each dietary intervention using a random-zero sphygmomanometer. Linear mixed-effect models were used to assess the additive associations of 63 tag singlenucleotide polymorphisms in 11 NADPH oxidase-related genes with BP responses to dietary sodium intervention. Gene-based analyses were conducted using the truncated product method. The Bonferroni method was used to adjust for multiple testing in all analyses. RESULTS Systolic BP (SBP) response to high-sodium intervention signifcantly decreased with the number of minor T allele of marker rs6967221 in RAC1 (P = 4.51 × 10). SBP responses (95% confdence interval) for genotypes CC, CT, and TT were 5.03 (4.71, 5.36), 4.20 (3.54, 4.85), and 0.56 (-1.08, 2.20) mm Hg, respectively, during the high-sodium intervention. Gene-based analyses revealed that RAC1 was signifcantly associated with SBP response to high-sodium intervention (P = 1.00 × 10) and diastolic BP response to low-sodium intervention (P = 9.80 × 10). CONCLUSIONS These fndings suggested that genetic variants of NADPH oxidaserelated genes may contribute to the variation of BP responses to sodium intervention in Chinese population. Further replication of these fndings is warranted.

Background The role of rare variants in blood pressure (BP) salt-sensitivity is unknown. We conducted a resequencing study of the renin-angiotensin-aldosterone system (RAAS) to identify rare variants associated with BP salt-sensitivity among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Methods The GenSalt study was conducted among 1,906 participants who underwent a 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding study (307.8 mmol sodium/day). The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study. Seven RAAS genes were resequenced using capillary-based sequencing methods. Rare variants were tested for association with BP salt-sensitivity using traditional burden tests. Single-marker analyses were employed to test associations of low-frequency and common variants. Results Aggregate rare variant analysis revealed an association of the RAAS pathway with BP salt-sensitivity. Carriers of rare RAAS variants had a 1.55-fold [95% confidence interval (CI): 1.15, 2.10] higher odds of salt-sensitivity compared to noncarriers (P = 0.004), a finding which was significant after Bonferroni correction. A nominal association of the APLN gene with salt-sensitivity was also identified, with rare APLN variants conferring a 2.22-fold (95% CI: 1.05, 6.58) higher odds of salt-sensitivity (P = 0.03). Single-marker analyses did not identify variant-BP salt-sensitivity associations after Bonferroni adjustment. A nominal association of a low-frequency, missense RENBP variant was identified. Each minor allele of rs78377269 conferred a 2.21-fold (95% CI: 1.10, 4.42) increased odds of salt-sensitivity (P = 0.03). Conclusions This study presents of the first evidence of a contribution of rare RAAS variants to BP salt-sensitivity. Clinical Trial RegistryTrial Number: NCT00721721.

BACKGROUND The large-scale meta-analysis of genome-wide association study (GWAS) recently identified a genomic locus where the genetic variant at rs820430 was strongly associated with hypertension in Chinese Han population, with its T allele conferred increased risks. However, the biological and disease-relevant mechanisms for this association remain elusive. METHODS A group of 275 participants from rural district of Shandong Province were enrolled, rs820430 was genotyped using genomic DNA with the fluorogenic 5'-nuclease TaqMan allelic discrimination assay system (Applied Biosystems, CA). In vitro experiments were performed in this study, such as luciferase reporter assays, gel mobility shift assays (electrophoretic mobility shift assay), and chromatin immunoprecipitation. RESULTS We found the risk T allele of rs820430 was associated with higher SLC4A7 mRNA level in cohort population. Furthermore, we characterized a cis-regulatory mechanism that the T allele of rs820430 distinctively increased c-Fos transcription factor binding, by which leading to increased SLC4A7 expression. CONCLUSIONS The present study indicated that the disease-associated T allele of a new hypertension risk variant rs820430 linked increased hypertension risk through higher SLC4A7 expression, and rs820430 functioned as an enhancer of SLC4A7 transcription by allele distinctively increased c-Fos transcription factor binding.

Background Single-marker and novel gene-based methods were employed to examine the associations of the serum/glucocorticoid regulated kinases (SGK) gene family with longitudinal blood pressure (BP) changes and hypertension incidence in a family-based cohort study. Methods Totally, 1,768 Chinese participants from the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study were included in the current analyses. Nine BP measures were obtained at each of 3 visits during the GenSalt follow-up study. Mixed-model and Gene-based analyses were used to examine the associations of the SGK gene family with longitudinal BP phenotypes. Bonferroni correction was applied to account for multiple testing. Results After an average 7.2-year follow-up, 32.2% (513) of participants free of hypertension at baseline developed hypertension. Four novel SNPs in the SGK1 gene were predictive of the longitudinal BP phenotypes. The major alleles of SGK1 rs1763498 and rs114414980 conferred 2.9- and 2.5-fold increased risks of hypertension development, respectively (P = 1.0×10-4 and 6.0×10-4, respectively). In addition, the major allele of SGK1 rs229133 was significantly associated with 0.4mm Hg larger annual increases in systolic BP (P = 4.2×10-4), while the major allele of rs6924468 was significantly associated with 0.2mm Hg smaller annual increases in diastolic BP (P = 4.2×10-4). Gene-based analyses revealed an association of the SGK1 gene with risk of hypertension development (P = 7.4×10-3). No evidence for the SGK2 and SGK3 genes was found. Conclusions The findings of the current study suggest that the SGK1 gene may play a role in long-term BP regulation and hypertension incidence.

BACKGROUND A resequencing study of renal epithelial sodium channel (ENaC) genes was conducted to identify rare variants associated with blood pressure (BP) salt-sensitivity. METHODS The Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study was conducted among 1,906 participants who underwent a 7-day low-sodium followed by a 7-day high-sodium feeding-study. The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study. Three ENaC genes (SCNN1A, SCNN1B, and SCNN1G) were resequenced using capillary-based sequencing methods. Traditional burden tests were utilized to examine association between rare variants and BP salt-sensitivity. Associations of low-frequency and common variants were tested using single-marker analyses. RESULTS Carriers of SCNN1A rare variants had a 0.52 [95% confidence interval (CI): 0.32–0.85] decreased odds of BP salt-sensitivity compared with noncarriers. Neither SCNN1B nor SCNN1G associated with salt-sensitivity of BP in rare variant analyses (P = 0.65 and 0.48, respectively). In single-marker analyses, 3 independent common variants in SCNN1A, rs11614164, rs4764586, and rs3741914, associated with salt-sensitivity after Bonferroni correction (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 (95% CI: 1.23–1.52) increased odds of salt-sensitivity, whereas each copy of the minor allele of rs11614164 and rs3741914 was associated with 0.68-fold (95% CI: 0.55–0.84) and 0.69-fold (95% CI: 0.54–0.86) decreased odds of salt-sensitivity, respectively. CONCLUSIONS This study demonstrated for the first time a relationship between rare variants in the ENaC pathway and BP salt-sensitivity. Future replication and functional studies are needed to confirm the findings in this study. CLINICAL TRIAL REGISTRY Trial Number NCT00721721

Hypertension is a major public health challenge worldwide due to its high prevalence and associated increases in risks of cardiovascular diseases.1,2 As the leading risk factor for mortality globally, approximately 13.5% of premature deaths were attributable to high blood pressure (BP) in 2001.2 High BP can be described as a complex trait, influenced by multiple environmental and genetic factors. Heritability studies indicate that about 30%–60% of interindividual variation in BP is genetically determined.3,4 Still, the genomic mechanisms underlying BP regulation remain largely unknown. Several reports have highlighted the importance of the endothelium on relaxing vascular smooth muscle and regulating vasomotor tone.5,6 Such findings suggest a potential role for endothelial dysfunction in the pathogenesis of hypertension. For example, studies have illustrated that endothelial-mediated vasodilatation is reduced not only in animal models of hypertension but also in humans with essential hypertension.7,8 These findings make endothelial system genes attractive candidates for genomic study of BP phenotypes. Several studies have already identified associations between genes encoding components of the endothelial system and prevalent hypertension.9–12 These studies have reported contributions of the endothelial nitric oxide synthase (NOS3), selectin E (SELE), endothelin receptor type A (EDNRA), and endothelin 1 (EDN1) genes to this complex phenotype.9–12 However, genomic research on longitudinal BP phenotypes, such as BP change over time and hypertension incidence, is limited. Only 4 studies of longitudinal BP traits have been conducted,10,13–15 including just 1 study conducted in East Asian participants.15 Furthermore, the previous studies examined only the NOS3 gene with inconsistent results.10,13–15 The paucity of research in this area highlights a need for additional study of the relation between endothelial system genes and longitudinal BP phenotypes. The present study was undertaken to determine whether common variants in endothelial system genes can predict BP changes or hypertension incidence among 1,768 Han Chinese participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study.

BACKGROUND The aim of this study was to comprehensively test the association of genetic variants in the natriuretic peptide (NP) system with blood pressure (BP) response to dietary sodium intervention in a Chinese population. METHODS We conducted a 7-day low-sodium intervention followed by a 7-day high-sodium intervention among 1,906 participants in rural China. BP measurements were obtained at baseline and each dietary intervention using a random-zero sphygmomanometer. Linear mixed-effect models were used to assess the associations of 48 single-nucleotide polymorphisms (SNPs) in 6 genes of NP system with BP response to dietary sodium intervention. RESULTS SNP rs5063 in the NPPA gene and SNP rs2077386 in the NPPC gene exhibited significant associations with BP response to low-sodium dietary intervention under recessive genetic model. For rs5063, absolute mean arterial pressure responses (95% confidence interval) to the low-sodium intervention were 1.31 (-1.08, 3.70) mm Hg for TT genotype and -3.74 (-4.01, -3.46) mm Hg for CC or TC genotype, respectively (P = 4.1 × 10(-5)). Individuals with at least one copy of the C allele of rs2077386 had significantly reduction in systolic BP during the low-sodium intervention compared to those with genotype GG with responses of -5.48 (-5.83, -5.14) vs. -2.76 (-3.52, -2.00) mm Hg, respectively (P = 1.9 × 10(-13)). CONCLUSIONS These novel findings suggested that genetic variants of NP system may contribute to the variation of BP response to sodium intervention in Chinese population. Certainly, replication of these results in other populations and further functional studies are warranted to clarify their role in the regulation of BP and hypertension.

Isolated systolic hypertension (ISH), more so than any other hypertension subtype, increases the risk for stroke and coronary heart disease. The prevalence of ISH versus other hypertension subtypes in the general Chinese adult population is not known.The prevalence of isolated systolic and isolated diastolic hypertension (IDH) was examined in a representative national sample of 15,540 Chinese adults aged 35 to 74 years. Three seated blood pressure (BP) measurements taken after 5 min of rest were averaged and hypertension subtypes were defined among individuals not receiving antihypertensive therapy as follows: ISH as systolic BP/=140 mm Hg and diastolic BP90 mm Hg; IDH as systolic BP140 mm Hg and diastolic BP/=90 mm Hg; and combined systolic/diastolic hypertension (SDH) as a systolic BP/=140 mm Hg and diastolic BP/=90 mm Hg.Overall, 7.6% of the Chinese adult population had ISH, 7.4% had SDH, and 4.4% had IDH. The prevalence of ISH increased with age and was more common in older women than in older men. Stage 1 hypertension was much more prevalent than stage 2 hypertension among all hypertension subtypes. The prevalence of SDH, IDH, and ISH (women, only) were higher in northern China than southern. The prevalence of ISH and SDH (women, only) were higher among rural residents versus urban residents.These data document high rates of ISH in China. Given the risk of cardiovascular disease associated with ISH, our findings underscore the critical need for enhanced hypertension screening and treatment programs in China.

BACKGROUND Blood pressure (BP) hyper-reactivity to the cold pressor test (CPT) has been suggested as a predictor of hypertension. We examined whether BP reactivity to the CPT was associated with hypertension incidence among the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study participants from China. METHODS A total of 1,961 GenSalt study participants without any antihypertensive treatment completed the CPT at the baseline examination. Hypertension status was assessed at baseline (2003-2005) and 2 follow-up visits (2008-2009 and 2011-2012). RESULTS After adjustment for multiple covariates, both systolic BP (SBP) and diastolic BP reactivity to the CPT were significantly associated with hypertension incidence. For example, the multivariable adjusted odds ratios (ORs, 95% CI) of developing hypertension were 0.92 (0.66, 1.29), 1.42 (1.03, 1.97), and 1.45 (1.05, 2.00) for participants with maximum SBP responses of 6.7-12.0, 12.1-19.2, and ≥19.3mm Hg, respectively, compared to those with responses of

We examined the associations of epithelial sodium channel (ENaC) genes with blood pressure (BP) changes and hypertension incidence in a longitudinal family study.A total of 2,755 Han Chinese participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) baseline examination were eligible for this study. The associations of 43 tag single nucleotide polymorphisms (SNPs) in ENaC genes with BP changes and hypertension incidence were assessed using mixed models to account for the correlations of repeated measures among individuals and within families. A genotype by time interaction term was used to model differences in longitudinal BP change according to genotype over time. Gene-based analyses were conducted using the truncated product method. The Bonferroni method was used to adjust for multiple testing in all analyses.During an average of 7.4 years follow-up, systolic BP (SBP) and diastolic BP (DBP) increased, and approximately 33% of participants developed hypertension. SCNN1A SNP rs11064153 and SCNN1G SNP rs4401050 were significantly associated with longitudinal changes in SBP after adjustment for multiple testing (P interaction = 5.8×10(-4) and 0.001, respectively). Similar but nonsignificant trends were observed for the associations between both rs11064153 and rs4401050 and DBP changes (P interaction = 0.024 and 0.005, respectively) and between rs11604153 and hypertension incidence (P = 0.02). Gene-based analyses also supported the overall association of SCNN1G with longitudinal changes in SBP (P = 2.0×10(-4)).Our findings indicated that SCNN1A and SCNN1G may contribute to BP changes over time in the Han Chinese population. Replication of these findings is warranted.

BACKGROUND Increased blood pressure (BP) reactivity to cold pressor test (CPT) is a risk factor for hypertension. Genetic factors may influence the variation of BP response to CPT among individuals. We explored the association of genetic variants in the apelin system genes (APLN, APLNR and ACE2) and BP response to CPT in a Chinese population. METHODS A total of 1,998 Han Chinese participants from the Genetic Epidemiology Network of Salt Sensitivity completed a CPT. The percentage changes of BP right after the end of ice-water immersion were used as the measurement of BP responses to CPT. Twenty-two single nucleotide polymorphisms (SNPs) were selected and genotyped, including both tag and potential functional SNPs of the APLN, APLNR, and ACE2 genes. A mixed-effect linear model was used to assess the association between SNPs and BP responses to CPT. RESULTS In women, three SNPs (rs1514283, rs4646176, and rs879922) of the ACE2 gene were significantly associated with the diastolic BP (DBP) response to CPT in the general and recessive genetic models after adjustment for multiple testing (all false discovery rate q < 0.05). There were no significant associations of polymorphisms in APLN and APLNR genes with BP responses to CPT. CONCLUSIONS Our study identified genetic variants in the ACE2 gene that were significantly associated with DBP responses to cold stress in the Chinese female population. Future studies are warranted to confirm these findings.

BACKGROUND Recently, fibrillin-1 (FBN1) was reported to play an important role in maintaining the physiological arterial stiffness of essential hypertension (EH). Here, we designed a two-stage case-control study to investigate whether the FBN1 gene harbored any genetic variations associated with EH. METHODS In stage 1, six candidate single-nucleotide polymorphisms (SNPs) of the FBN1 gene were genotyped and tested in 503 cases and 490 controls. SNPs associated with EH (P < 0.05) in stage 1 would be genotyped in stage 2 (814 cases and 779 controls), and analyzed in all the individuals by allele, genotype, haplotype, and diplotype. A meta-analysis was performed and inverse-variance method with random effect model was employed to estimate combined odds ratio (OR) and its 95% confidence interval (CI) for the identified SNPs. RESULTS In stage 1, rs140598 and rs6493333 had statistical association with EH (P < 0.05) and enter stage 2. Multiple logistic regression analysis confirmed that rs140598 but not rs6493333 significantly associated with EH in stage 2 sample. Meta-analysis showed that there was nearly no heterogeneity (I(2) = 0) of genetic variance of rs140598 in the two stages, and the associations of rs140598 in all three genetic models presented statistical significance. Further haplotype analyses showed that the Hap2 (G-C) might decreased the risk of EH when compared with reference haplotype Hap1 (C-C), adjusted OR (95%CI) was 0.823 (0.715-0.948), P = 0.006. CONCLUSION Our finding suggested there is a significant association of rs140598 of FBN1 gene with EH and further replication in other population for association study or prospective study should be warranted.

We examined the relationship between systolic and diastolic blood pressure (BP) and the incidence of cardiovascular disease (CVD) in a nationally representative cohort of 169,871 men and womenor = 40 years of age in China.Data on BP and other variables were obtained at a baseline examination in 1991 using standard protocols. Follow-up evaluation was conducted in 1999-2000, with a response rate of 93.4%.After adjustment for age, sex, cigarette smoking, alcohol consumption, physical activity, body mass index, education, geographic region, urbanization, and time-dependent history of diabetes, a strong and linear association between both systolic and diastolic BP and incidence of CVD, coronary heart disease and stroke were observed (all P0.0001). For example, the relative risks (95% confidence interval (CI)) of CVD incidence were 1.09 (1.00-1.18), 1.25 (1.16-1.35), 1.49 (1.38-1.62), 2.15 (1.99-2.31), 3.01 (2.78-3.27), and 4.16 (3.84-4.51) for those with systolic/diastolic BP of 110-119/75-79, 120-129/80-84, 130-139/85-89, 140-159/90-99, 160-179/100-109, andor = 180/110 mm Hg compared to those with BP110/75 mm Hg. Increases in systolic BP were associated with a greater risk of CVD compared to corresponding increases in diastolic BP. The linear trend for increased CVD risk being related to higher BP levels was observed in all subgroups of gender, age, body weight, and cigarette smoking.Our results indicate that there is a strong, linear, and independent relationship between BP levels and the risk of CVD in Chinese adults. Systolic BP is a stronger predictor of CVD risk compared to diastolic BP.