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Background: Blood pressure responses to dietary sodium intake vary among individuals. However, it is unknown whether sodium sensitivity and sodium resistance predict incidence of hypertension. Methods: We conducted a feeding study, including a 7-day low-sodium diet (51.3 mmol/day) and a 7-day high-sodium diet (307.8 mmol/day), among 1,718 Chinese individuals with normal blood pressure in 2003-2005 and follow-up studies in 2008-2009 and 2011-2012. Three blood-pressure measurements and 24-hour urinary sodium excretion were obtained on each of 3 days during baseline, low- and high-sodium interventions, and follow-up visits. Latent class models were used to identify subgroups that share a similar underlying trajectory in blood-pressure responses to dietary sodium intake. Results: Three trajectories of systolic blood pressure responses to dietary sodium intake were identified (Figure). Mean (standard deviation) changes in systolic blood pressure were -13.7 (5.5), -4.9 (3.0), and 2.4 (3.0) mmHg during the low-sodium intervention, and 11.2 (5.3), 4.4 (4.1) and -0.2 (4.1) mmHg during the high-sodium intervention ( P< 0.001 for group differences) in high sodium-sensitive, moderate sodium-sensitive, and sodium-resistant groups, respectively. Compared to individuals with moderate sodium sensitivity, multiple-adjusted odds ratio (95% confidence intervals) for incident hypertension were 1.44 (1.03 to 1.99) for those with high sodium sensitivity and 1.42 (1.02 to 1.97) for those with sodium resistance ( P P Conclusions: Individuals with either high sodium sensitivity or sodium resistance are at an increased risk for developing hypertension.

Background: The accurate assessment of individual risk can be of great value to guiding and facilitating the prevention of atherosclerotic cardiovascular disease (ASCVD). However, prediction models in common use were formulated primarily in white populations. The China-PAR project (Prediction for ASCVD Risk in China) is aimed at developing and validating 10-year risk prediction equations for ASCVD from 4 contemporary Chinese cohorts. Methods: Two prospective studies followed up together with a unified protocol were used as the derivation cohort to develop 10-year ASCVD risk equations in 21 320 Chinese participants. The external validation was evaluated in 2 independent Chinese cohorts with 14 123 and 70 838 participants. Furthermore, model performance was compared with the Pooled Cohort Equations reported in the American College of Cardiology/American Heart Association guideline. Results: Over 12 years of follow-up in the derivation cohort with 21 320 Chinese participants, 1048 subjects developed a first ASCVD event. Sex-specific equations had C statistics of 0.794 (95% confidence interval, 0.775–0.814) for men and 0.811 (95% confidence interval, 0.787–0.835) for women. The predicted rates were similar to the observed rates, as indicated by a calibration χ 2 of 13.1 for men ( P =0.16) and 12.8 for women ( P =0.17). Good internal and external validations of our equations were achieved in subsequent analyses. Compared with the Chinese equations, the Pooled Cohort Equations had lower C statistics and much higher calibration χ 2 values in men. Conclusions: Our project developed effective tools with good performance for 10-year ASCVD risk prediction among a Chinese population that will help to improve the primary prevention and management of cardiovascular disease.

Christopher E. Anderson, Changwei Li, Jiang He, Dongfeng Gu, Dabeeru C. Rao, James E. Hixson, Lawrence C. Shimmin, Jianfeng Huang, Charles C. Gu, Jichun Chen, Jianxin Li, Tanika N. Kelly Genetic association studies have identified significant associations between common variants from the epithelial sodium channel (ENaC) genes and blood pressure responses to dietary sodium interventions. The roles of low-frequency and rare ENaC variants in blood pressure salt-sensitivity remain largely unexplored. To test this hypothesis, we conducted an ENaC candidate gene resequencing study among participants in the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt). The GenSalt study was conducted among 1,906 participants from 633 families who underwent a 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium (307.8 mmol sodium/day) feeding-study. We chose the 300 GenSalt subjects with the highest and 300 GenSalt subjects with the lowest mean arterial pressure responses to the high sodium intervention to participate in the current resequencing study. Functional regions of three ENaC subunit genes ( SCNN1A , SCNN1B and SCNN1G ) were resequenced using the VariantSEQr TM system (Applied Biosystems; Foster City, CA). For gene-based analyses, variants with MAF less than 5% were first collapsed within each ENaC gene. The collapsed indicator variable was then tested for association with blood pressure salt-sensitivity using generalized estimating equations (GEE) to accommodate correlation of genotypes due to family structure and adjust for the fixed effects of age, gender and field center. Single variant analyses were performed for all low-frequency variants with a minor allele frequency (MAF) greater than 1% and less than 5%, again using GEE to accommodate family structure and adjust for covariables. We did not identify any associations between ENaC genes and blood pressure salt-sensitivity in the gene-based analyses. However, single variant analysis identified a novel association between a low-frequency variant in SCNN1G , rs148083677, and blood pressure salt-sensitivity (P=0.02). Each minor allele was associated with 71% lower odds of blood pressure salt-sensitivity. Although replication studies are needed, these findings provide promising evidence of a role for low-frequency ENaC variants in blood pressure salt-sensitivity.

Background: The current study aimed to identify genes and variants influencing BP regulation by conducting genomewide single-marker and gene-based analyses of gene-potassium interactions among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Methods: GenSalt recruited 1,906 Chinese participants from 633 families. At baseline, one 24-hour and two 8-hour urine specimens were collected to measure urinary potassium excretion. Nine BP measurements were taken using a random zero sphygmomanometer. A total of 868,158 autosomal SNPs were genotyped using Affymetrix Genomewide Human SNP array 6.0 (Affymetrix, Inc, Santa Clara, CA). Mixed effects models were used to test genome-wide 1 degree-of-freedom (df) SNP-potassium interactions and 2 df joint effects on BP, adjusting for age, gender, and body mass index. The GATES method was used to perform genome-wide gene-based analyses. Promising findings ( P -4 ) from GenSalt were evaluated for replication among Chinese participants of the Multi-Ethnic Study of Atherosclerosis (MESA). SNP and gene effects were meta-analyzed across GenSalt and MESA studies. Results: The SNP based analyses identified 7 novel loci that significantly interacted with potassium to influence BP. The 1 df tests identified interactions for BNC variant rs16934920 on DBP (GenSalt P =1.07х10 -6 , MESA P =2.64х10 -3 , and Meta-analysis P = 2.31х10 -8 ) and MAP (GenSalt P =2.38х10 -8 , MESA P =2.08х10 -2 , and Meta-analysis P = 1.57х10 -9 ), and intergenic variant rs13210180 on PP (GenSalt P =2.43х10 -7 , MESA P =9.39х10 -3 , and Meta-analysis P = 4.24х10 -8 ). The 2 df joint tests additionally identified interactions for ANKMY1 variant rs6741340 (GenSalt P =4.43х10 -8 , MESA P =1.90х10 -2 , and Meta-analysis P = 1.04х10 -9 ) on SBP, intergenic variant rs2101828 on DBP (GenSalt P =6.96х10 -9 , MESA P =2.21х10 -2 , and Meta-analysis P = 6.52х10 -11 ) and MAP (GenSalt P =6.26х10 -11 , MESA P =1.20х10 -2 , and Meta-analysis P = 2.22х10 -13 ), and MTR variant rs10495384 (GenSalt P =1.44х10 -6 , MESA P =2.69х10 -2 , and Meta-analysis P = 3.11х10 -8 ), intergenic variants rs9815615 (GenSalt P =5.55х10 -7 , MESA P =1.00х10 -10 , and Meta-analysis P = 4.47х10 -19 ), and LINC00379 variant rs9583894 (GenSalt P =2.10х10 -8 , MESA P =4.31х10 -2 , and Meta-analysis P = 1.32х10 -9 ) on PP. Genomewide gene-based analysis of the 1 df and 2 df tests identified ACOT7 at 1p36.31, DAB1 at 1p32.2, PDK1 at 2q31.1, TRPM8 at 2q37.1, EGFEM1P at 3q26.2, EPHA6 at 3q11.2, CPEB2 at 4p15.33, FBXL17 at 5q21.3, RANBP3L at 5p13.2, ARID1B at 6q25.3, C6orf165 at 6q15, GGNBP1 at 6p21.31, BNC2 at 9p22.3, CUTC at 10q24.2, ARHGAP42 at 11q22.1, LINC00379 at 13q31.3, MTUS2 at 13q12.3, TMTC4 at 13q32.3, and SERPINA6 at 14q32.13 that were associated with at least one BP phenotype. Conclusion: The current study identified 7 novel loci and 19 genes which may interact with dietary potassium intake to influence BP phenotypes.

Background— We examined the relationship between hypertension subtype and cardiovascular disease incidence and mortality in Chinese adults. Methods and Results— We conducted a prospective cohort study in a nationally representative sample of 169 871 Chinese men and women aged ≥40 years. Data on systolic (SBP) and diastolic blood pressure (DBP) and other variables were obtained at a baseline examination in 1991 with the use of standard protocols. Follow-up evaluation was conducted in 1999–2000, with a response rate of 93.4%. Hypertension subtypes were defined as combined systolic and diastolic hypertension (SBP ≥140 and DBP ≥90 mm Hg), isolated systolic hypertension (SBP ≥140 and DBP Conclusions— Our results indicate that all hypertension subtypes are associated with significantly increased risk of cardiovascular disease in Chinese adults. Primary prevention of hypertension should be a public health priority in the Chinese population.

Background: Elevated blood pressure (BP) is a major public health challenge. Although the heritability of BP has been long established, current findings can explain only a small proportion of the BP variability attributed to genetic factors. Recent studies indicate that gene-environmental interactions may help to identify novel BP loci. Hence, the current study aimed to identify genetic variants influencing BP regulation by conducting genome-wide gene-sodium interaction analyses among 1,906 participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Methods: GenSalt recruited 1,906 Chinese participants from 633 families. At baseline, one 24-hour and two 8-hour urine specimens were collected to measure urinary sodium excretion. Nine BP measurements were taken using a random zero sphygmomanometer. A total of 868,158 autosomal single nucleotide polymorphisms (SNPs) were genotyped using Affymetrix Genomewide Human SNP array 6.0 (Affymetrix, Inc, Santa Clara, CA). Mixed effects models were used to test genome-wide SNP-sodium interactions on BP, adjusting for age, gender, and body mass index. Promising findings (interaction term P -6 ) from GenSalt were further evaluated for replication among Chinese participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with available data from the database of genotypes and phenotypes (dbGaP). SNP effects in GenSalt and MESA were meta-analyzed using inverse-variance weighted fixed effect models. Results: The meta-analyses identified 3 novel loci that significantly interacted with sodium to influence BP phenotypes. SNP-sodium interactions on systolic BP were identified for NEK2 variant rs10494938 at 1q32.3 (GenSalt P =2.19х10 -6 , MESA P =4.35х10 -4 , and Meta-analysis P = 3.93х10 -8 ). In addition, CASP4 variant rs1944900 at 11q22.3 interacted with sodium to influence both systolic BP (GenSalt P =1.24х10 -9 , MESA P =4.22х10 -2 , and Meta-analysis P = 1.14х10 -10 ) and mean arterial pressure (GenSalt P =1.68х10 -9 , MESA P =4.27х10 -2 , and Meta-analysis P = 1.91х10 -10 ). Furthermore, C9orf3 variant rs17679141 at 9q22.32 interacted with sodium to influence diastolic BP (GenSalt P =2.85х10 -8 , MESA P =4.55х10 -2 , and Meta-analysis P =4.61х10 -9 ). The 3 variants all physically mapped to the intronic regions of their corresponding genes. Conclusion: The current study identified 3 novel loci which may interact with dietary sodium intake to influence BP phenotypes.

Background: Serum and glucocorticoid regulated kinase (SGK) plays a critical role in the regulation of renal sodium transport. We examined the association between SGK genes and salt sensitivity of blood pressure (BP) using single-marker and gene-based association analyses. Methods: A 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium intervention (307.8 mmol sodium/day) was conducted among 1,906 Chinese participants. BP measurements were obtained at baseline and each intervention using a random-zero sphygmomanometer. Additive associations between each SNP and salt-sensitivity phenotypes were assessed using a mixed linear regression model to account for family dependencies. Gene-based analyses were conducted using the truncated p-value method. The Bonferroni-method was used to adjust for multiple testing in all analyses. Results: In single-marker association analyses, SGK1 marker rs2758151 was significantly associated with diastolic BP (DBP) response to high-sodium intervention (P=0.0010). DBP responses (95% confidence interval) to high-sodium intervention for genotypes C/C, C/T, and T/T were 2.04 (1.57 to 2.52), 1.79 (1.42 to 2.16), and 0.85 (0.30 to 1.41) mmHg, respectively. Similar non-significant trends were observed for SBP and MAP responses (P=0.15 and 0.0026, respectively). In addition, gene-based analyses demonstrated significant associations between SGK1 and SBP, DBP and MAP responses to high sodium intervention (P=0.0002, 0.0076, and 0.00001, respectively). Neither SGK2 nor SGK3 were associated with the salt-sensitivity phenotypes in single-maker and gene-based analyses. Conclusions: The current study identified single-marker and gene-based association of the SGK1 gene and BP salt-sensitivity in the Han Chinese population. Further studies are warranted to identify causal SGK1 gene variants.

It is well known that blood pressure (BP) responses to dietary sodium and potassium intakes vary among individuals (salt- and potassium-sensitivity). However, it is unknown whether salt- and/or potassium-sensitivity predict the risk of hypertension. We conducted a dietary sodium and potassium intervention study among 1,906 Han Chinese in 2003-05 and followed the study participants in 2008-09 and 2011-12. The dietary intervention included a 7-day low sodium-feeding (51.3 mmol/day), a 7-day high sodium-feeding (307.8 mmol/day), and a 7-day high sodium-feeding with an oral potassium supplementation (60 mmol/day). Three BP measurements were obtained on each of the last 3 days of each intervention period at the baseline and each of the 3 days of follow-up examinations. Systolic BP responses (mean ± SD) to dietary intervention were -5.5±7.0 for low-sodium, 4.9±6.0 for high-sodium, and -3.5±5.5 for potassium-supplementation. Over an average of 7.4 years of follow-up, we identified 455 incidence hypertension cases (systolic BP≥140 mmHg and/or diastolic BP ≥90 mmHg and/or use of antihypertensive medication). The age-adjusted cumulative incidences of hypertension by the quartiles of systolic BP responses to dietary intervention were showed in the following table. These associations remained after adjustment for multiple covariates. These data indicate that BP responses to dietary sodium and potassium intervention are related to the subsequent risk of hypertension. Furthermore, our study suggests that individuals who are more sensitive to dietary sodium and potassium intake are at an increased risk for hypertension and should be target for dietary intervention.

The cold pressor test (CPT), which measures the response of blood pressure (BP) to the stimulus of external cold, has long been a standard test to characterize sympathetic nervous system activity and has been documented to predict cardiovascular risk. We conducted a CPT among 1,998 Han Chinese in 2003-05 and followed the study participants in 2008-09 and 2011-12 for incidence of hypertension. CPT was conducted after the participant had remained sitting for 20 minutes. The participant immersed his or her left hand in the ice water bath (3°C to 5°C) for 1 minute and BP measurements at 0, 60, 120, and 240 seconds were obtained after the left hand had been removed from the ice water bath. During the follow-up examinations, 3 BP measurements were obtained on each of 3 clinical visits. The maximum and area-under-curve (AUC) of systolic BP responses (mean ± SD) to CPT were 13.9±10.2 and 17.1±22.9 at the baseline examination. Over an average of 7.4 years of follow-up, we identified 490 incidence hypertension cases (systolic BP≥140 mmHg and/or diastolic BP ≥90 mmHg and/or use of antihypertensive medication). The age-adjusted cumulative incidences of hypertension by the quartiles of systolic BP responses to CPT were showed in the following table. These associations remained after adjustment for multiple covariates. Our study identified a strong and independent association between BP responses to CPT and subsequent incidence of hypertension. These data suggest that increased sympathetic nervous system activity may play a role in the development of hypertension.

Blood pressure (BP) responses to dietary sodium and potassium interventions vary among individuals (salt- and potassium-sensitivity). However, it is unknown whether salt- and/or potassium-sensitivity is a reproducible trait. We repeated the dietary sodium and potassium intervention among 488 Han Chinese who participated in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) four years after the original dietary intervention. The same dietary intervention protocol, which included a 7-day low sodium-feeding (51.3 mmol/day), a 7-day high sodium-feeding (307.8 mmol/day), and a 7-day high sodium-feeding with an oral potassium supplementation (60 mmol/day), was applied in both the original and repeated studies. Three BP measurements were obtained during each of the 3 days of baseline observation and on days 5, 6, and 7 of each intervention period. Three timed urinary samples were collected to measure sodium and potassium excretion at baseline and during each intervention phase. On average, study participants were 39.7 years old and 49.4% of them were male. Study participants had a mean body mass index of 23.7 kg/m 2 , systolic BP of 118.1 mmHg, diastolic BP of 74.4 mmHg, urinary excretion of sodium of 258.8 mmol/24-hrs, and urinary excretion of potassium of 38.8 mmol/24-hrs. The results from the 24-h urinary excretions of sodium and potassium showed excellent compliance with the study diet. BP responses to dietary intervention in the original and repeated studies were highly correlated. For example, the correlation coefficients for systolic BP between original and repeated studies were 0.7681 at baseline, 0.7902 during low-sodium, 0.8045 during high-sodium, and 0.8232 during high-sodium and potassium supplementation intervention (all p

Higher blood pressure (BP) response to cold pressor test (CPT) is associated with increased risk of hypertension and cardiovascular diseases. However, it is unknown whether BP response to CPT is a stable and reproducible trait. We repeated the CPT among 568 Han Chinese who participated in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) four years after the original study. The same CPT protocol was applied in the original and repeated studies. BP was measured prior to and at 0, 1, 2, and 4 minutes after the participants immersed their hand in ice water (3 o C to 5 o C) for 1 minute using a standard mercury sphygmomanometer. On average, study participants were 39.0 years old and 54.0% of them were male. The mean body mass index was 23.6 kg/m 2 , systolic BP was 117.8 mmHg, and diastolic BP was 74.5 mmHg at baseline among study participants. The mean (standard deviation) of systolic BP responses at time 0 and 1 minutes, maximum responses, and area-under-the-curve during CPT were 13.3 (10.1), 4.2 (6.0), 13.6 (9.8) and 10.8 (17.6) mmHg in the original study and 11.1 (9.5), 4.1 (6.0), 11.7 (8.9), and 10.1 (17.1) mmHg in the repeated study. BP responses in the original and repeated studies were highly correlated. For example, the correlation coefficients for systolic BP responses to CPT were 0.4137 at time 0 minute, 0.3711 at time 1 minute, 0.4221 for the maximum responses, and 0.3641 for area-under-the-curve during CPT (all p