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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.

Cardiovascular disease (CVD) is the leading cause of death in the United States and the world. Clinical trials have suggested that soybean protein lowers lipids and blood pressure. The effect of soybean protein on novel CVD risk factors has not been well studied. The objective of this study was to examine the effect of soybean protein on biomarkers of inflammation, endothelial dysfunction and adipocytokines. The effect of 8 weeks of 40 g of soybean protein supplement (89.3 mg isoflavones), 40 g of milk protein supplement and 40 g of complex carbohydrate placebo was examined in a randomized, placebo-controlled, double-blind, three-phase crossover trial among adults in New Orleans, Louisiana and Jackson, Mississippi. Plasma levels of inflammation biomarkers (C-reactive protein, interleukin-6, tumor necrosis factor-α), endothelial dysfunction biomarkers (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, thrombomodulin) and adipocytokines (high-molecular weight adiponectin, leptin, resistin) were measured at baseline and at the end of each intervention using immunoturbidimetric and enzyme-linked immunosorbent assay techniques. Soy protein supplementation resulted in a significant mean net change (95% confidence interval) in plasma E-selectin of −3.93 ng/ml (−7.05 to −0.81 ng/ml; P=0.014) compared with milk protein, and in plasma leptin of −2089.8 pg/ml (−3689.3 to −490.3 pg/ml; P=0.011) compared with carbohydrate. There were no significant changes in any other risk factors. Soy protein supplementation may reduce levels of E-selectin and leptin. Further research is warranted to investigate the mechanisms through which protein may confer protective effects on novel CVD risk factors.

The current study comprehensively examined the association between common genetic variants of the kallikrein-kinin system (KKS) and blood pressure salt sensitivity. A 7-day low-sodium followed by a 7-day high-sodium dietary intervention was conducted among 1,906 Han Chinese participants recruited from 2003 to 2005. Blood pressure was measured by using a random-zero sphygmomanometer through the study. A total of 205 single nucleotide polymorphisms (SNPs) covering 11 genes of the KKS were selected for the analyses. Genetic variants of the bradykinin receptor B2 gene (BDKRB2) and the endothelin converting enzyme 1 gene (ECE1) showed significant associations with the salt-sensitivity phenotypes even after adjustment for multiple testing. Compared with the major G allele, the BDKRB2 rs11847625 minor C allele was significantly associated with increased systolic blood pressure responses to low-sodium intervention (P = 0.0001). Furthermore, a haplotype containing allele C was associated with an increased systolic blood pressure response to high-sodium intervention (P = 0.0009). Seven highly correlated ECE1 SNPs were shown to increase the diastolic blood pressure response to low-sodium intervention (P values ranged from 0.0003 to 0.002), with 2 haplotypes containing these 7 SNPs also associated with this same phenotype (P values ranged from 0.0004 to 0.002). In summary, genetic variants of the genes involved in the regulation of KKS may contribute to the salt sensitivity of blood pressure.

The relation between parental history of hypertension and blood pressure response to potassium intake is unknown. A 7-day high-sodium followed by a 7-day high-sodium plus potassium dietary-feeding study was conducted from 2003 to 2005 among 1,871 Chinese participants. Those with a maternal history of hypertension had larger systolic blood pressure responses to potassium compared with those without: -4.31 (95% confidence interval (CI): -4.99, -3.62) mm Hg versus -3.35 (95% CI: -4.00, -2.70) mm Hg, respectively (P(difference) = 0.002). A consistent trend was observed for diastolic blood pressure responses: -1.80 (95% CI: -2.41, -1.20) mm Hg versus -1.35 (95% CI: -1.95, -0.74) mm Hg, respectively (P = 0.07). Stronger associations between early onset maternal hypertension and blood pressure responses were noted, with systolic blood pressure decreases of -4.80 (95% CI: -5.65, -3.95) mm Hg versus -3.55 (95% CI: -4.17, -2.93) mm Hg and diastolic blood pressure decreases of -2.25 (95% CI: -3.01, -1.50) mm Hg versus -1.42 (95% CI: -1.99, -0.85) mm Hg among those with early onset maternal hypertension versus those without, respectively (P = 0.001 and 0.009, respectively). Odds ratios for high potassium sensitivity were 1.36 (95% CI: 0.96, 1.92) and 1.60 (95% CI: 1.08, 2.36) for those with maternal hypertension and early onset maternal hypertension, respectively (P = 0.08 and 0.02, respectively). Potassium supplementation could help to reduce blood pressure among those with a maternal history of hypertension.

The effects of low-carbohydrate diets (≤45% of energy from carbohydrates) versus low-fat diets (≤30% of energy from fat) on metabolic risk factors were compared in a meta-analysis of randomized controlled trials. Twenty-three trials from multiple countries with a total of 2,788 participants met the predetermined eligibility criteria (from January 1, 1966 to June 20, 2011) and were included in the analyses. Data abstraction was conducted in duplicate by independent investigators. Both low-carbohydrate and low-fat diets lowered weight and improved metabolic risk factors. Compared with participants on low-fat diets, persons on low-carbohydrate diets experienced a slightly but statistically significantly lower reduction in total cholesterol (2.7 mg/dL; 95% confidence interval: 0.8, 4.6), and low density lipoprotein cholesterol (3.7 mg/dL; 95% confidence interval: 1.0, 6.4), but a greater increase in high density lipoprotein cholesterol (3.3 mg/dL; 95% confidence interval: 1.9, 4.7) and a greater decrease in triglycerides (-14.0 mg/dL; 95% confidence interval: -19.4, -8.7). Reductions in body weight, waist circumference and other metabolic risk factors were not significantly different between the 2 diets. These findings suggest that low-carbohydrate diets are at least as effective as low-fat diets at reducing weight and improving metabolic risk factors. Low-carbohydrate diets could be recommended to obese persons with abnormal metabolic risk factors for the purpose of weight loss. Studies demonstrating long-term effects of low-carbohydrate diets on cardiovascular events were warranted.

The authors conducted a genome-wide linkage scan and positional association analysis to identify the genetic determinants of salt sensitivity of blood pressure (BP) in a large family-based, dietary-feeding study. The dietary intervention was conducted among 1,906 participants in rural China (2003-2005). A 7-day low-sodium intervention was followed by a 7-day high-sodium intervention. Salt sensitivity was defined as BP responses to low- and high-sodium interventions. Signals of the logarithm of the odds to the base 10 (LOD ≥ 3) were detected at 33-42 centimorgans of chromosome 2 (2p24.3-2p24.1), with a maximum LOD score of 3.33 for diastolic blood pressure responses to high-sodium intervention. LOD scores were 2.35-2.91 for mean arterial pressure (MAP) and 0.80-1.49 for systolic blood pressure responses in this region, respectively. Correcting for multiple tests, single nucleotide polymorphism (SNP) rs11674786 (2.7 kilobases upstream of the family with sequence similarity 84, member A, gene (FAM84A)) in the linkage region was significantly associated with diastolic blood pressure (P = 0.0007) and MAP responses (P = 0.0007), and SNP rs16983422 (2.8 kilobases upstream of the visinin-like 1 gene (VSNL1)) was marginally associated with diastolic blood pressure (P = 0.005) and MAP responses (P = 0.005). An additive interaction between SNPs rs11674786 and rs16983422 was observed, with P = 7.00 × 10(-5) and P = 7.23 × 10(-5) for diastolic blood pressure and MAP responses, respectively. The authors concluded that genetic region 2p24.3-2p24.1 might harbor functional variants for the salt sensitivity of BP.

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 × 10(-8)) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 × 10(-31) and P = 1.3 × 10(-35) for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.

Background: A region-specific (urban and rural parts of north, east, west, and south India) systematic review and meta-analysis of the prevalence, awareness, and control of hypertension among Indian patients have not been done before. Methods: Medline, Web of Science, and Scopus databases from 1950 to 30 April 2013 were searched for ‘prevalence, burden, awareness, and control of blood pressure (BP) or hypertension (≥140 SBP and or ≥90 DBP) among Indian adults’ (≥18 years). Of the total 3047 articles, 142 were included. Results: Overall prevalence for hypertension in India was 29.8% (95% confidence interval: 26.7–33.0). Significant differences in hypertension prevalence were noted between rural and urban parts [27.6% (23.2–32.0) and 33.8% (29.7–37.8); P = 0.05]. Regional estimates for the prevalence of hypertension were as follows: 14.5% (13.3–15.7), 31.7% (30.2–33.3), 18.1% (16.9–19.2), and 21.1% (20.1–22.0) for rural north, east, west, and south India; and 28.8% (26.9–30.8), 34.5% (32.6–36.5), 35.8% (35.2–36.5), and 31.8% (30.4–33.1) for urban north, east, west, and south India, respectively. Overall estimates for the prevalence of awareness, treatment, and control of BP were 25.3% (21.4–29.3), 25.1% (17.0–33.1), and 10.7% (6.5–15.0) for rural Indians; and 42.0% (35.2–48.9), 37.6% (24.0–51.2), and 20.2% (11.6–28.7) for urban Indians. Conclusion: About 33% urban and 25% rural Indians are hypertensive. Of these, 25% rural and 42% urban Indians are aware of their hypertensive status. Only 25% rural and 38% of urban Indians are being treated for hypertension. One-tenth of rural and one-fifth of urban Indian hypertensive population have their BP under control.

Background— Genetic determinants of blood pressure (BP) response to potassium, or potassium sensitivity, are largely unknown. We conducted a genome-wide linkage scan and positional candidate gene analysis to identify genetic determinants of potassium sensitivity. Methods and Results— A total of 1906 Han Chinese participants took part in a 7-day high-sodium diet followed by a 7-day high-sodium plus potassium dietary intervention. BP measurements were obtained at baseline and after each intervention using a random-zero sphygmomanometer. Significant linkage signals (logarithm of odds [LOD] score, >3) for BP responses to potassium were detected at chromosomal regions 3q24-q26.1, 3q28, and 11q22.3-q24.3. Maximum multipoint LOD scores of 3.09 at 3q25.2 and 3.41 at 11q23.3 were observed for absolute diastolic BP (DBP) and mean arterial pressure (MAP) responses, respectively. Linkage peaks of 3.56 at 3q25.1 and 3.01 at 11q23.3 for percent DBP response and 3.22 at 3q25.2, 3.01 at 3q28, and 4.48 at 11q23.3 for percent MAP response also were identified. Angiotensin II receptor, type 1 ( AGTR1 ), single-nucleotide polymorphism rs16860760 in the 3q24-q26.1 region was significantly associated with absolute and percent systolic BP responses to potassium ( P =0.0008 and P =0.0006, respectively). Absolute (95% CI) systolic BP responses for genotypes C/C, C/T, and T/T were −3.71 (−4.02 to −3.40), −2.62 (−3.38 to −1.85), and 1.03 (−3.73 to 5.79) mm Hg, respectively, and percent responses (95% CI) were −3.07 (−3.33 to −2.80), −2.07 (−2.74 to −1.41), and 0.90 (−3.20 to 4.99), respectively. Similar trends were observed for DBP and MAP responses. Conclusions— Genetic regions on chromosomes 3 and 11 may harbor important susceptibility loci for potassium sensitivity. Furthermore, the AGTR1 gene was a significant predictor of BP responses to potassium intake. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00721721.

We examined the genetic association between blood pressure (BP) responses to dietary sodium and potassium intervention and to cold pressor test (CPT) in a large family-based dietary feeding study. The dietary intervention and CPT were conducted among 1906 participants in rural China. The dietary intervention included three 7-day periods of low-sodium feeding (51.3 mmol per day), high-sodium feeding (307.8 mmol per day) and high-sodium feeding plus potassium supplementation (60 mmol per day). BP responses to high-sodium intervention had strong genetic correlations (ρ(G)) with both BP responses to low sodium (ρ(G)=-0.43 to -0.54, P-values=0.0005 to 0.03) and to potassium supplementation (ρ(G)=-0.41 to -0.49, P-values=0.001 to 0.005) interventions. Most environmental correlations between BP responses to various dietary interventions were significant. The ρ(G) between BP responses to CPT and to high-sodium intervention and potassium supplementation were statistically significant. For example, the ρ(G) between maximum BP responses to CPT and BP responses to high-sodium intervention was 0.37 (P=0.006) for systolic BP (SBP) and 0.41 (P=0.002) for diastolic BP (DBP). The ρ(G) between maximum BP responses to CPT and BP responses to potassium intervention was -0.42 (P=0.001) for SBP and -0.46 (P=0.001) for SBP. Our study suggests that there are common genetic determinants that influence BP responses to dietary sodium and potassium interventions and to CPT.

Objective To examine the association between renin-angiotensin-aldosterone system (RAAS) genes and salt sensitivity of blood pressure (BP). Methods A 7-day low-sodium dietary intervention followed by a 7-day high-sodium dietary intervention was conducted among 1906 participants living in a rural region of north China where habitual sodium intake is high. BP measurements were obtained at baseline and following each intervention using a random-zero sphygmomanometer. Results DBP and mean arterial pressure responses increased with the number of rs4524238 A alleles in the angiotensin II receptor type 1 gene. For example, mean DBP responses (95% confidence interval) among those with genotypes G/G, G/A, and A/A were -2.53 (-2.89 to -2.18), -3.49 (-4.13 to -2.86), and -5.78 (-9.51 to -2.06) mmHg, respectively, following the low-sodium intervention (P=0.0008). Carriers of the rare A allele of rs5479 in the hydroxysteroid (11-beta) dehydrogenase 2 gene had decreased DBP responses to low sodium (P=0.00004). Those with the C/A and C/C genotypes had DBP responses of -0.70 (-6.62 to 5.22) and -2.71 (-4.88 to -0.54) mmHg, respectively. X chromosome renin-binding protein gene markers rs1557501 and rs2269372 were associated with SBP response to low sodium in men (P=0.00004 and 0.0001, respectively). SBP responses (95% confidence interval) were -6.13 (-6.68 to -5.58) versus -4.07 (-4.88 to -3.26) and -6.04 (-6.57 to -5.52) versus -3.94 (-4.90 to -2.99) mmHg among men with major versus those with minor alleles of rs1557501 and rs2269372, respectively. Haplotype analyses of these genes supported our single-marker findings. Conclusion We identified renin-angiotensin-aldosterone system variants that were predictive of salt sensitivity in a Han population with habitually high-sodium intake.

Although beneficial effects of potassium intake on blood pressure (BP) are well established, little is known about genetic factors that underlie interindividual variability in BP response to dietary potassium. In a previous study, we reported the first evidence for significant heritabilities for BP response in a dietary intervention study in rural Chinese. In this report, we extend our genetic studies to examine associations with polymorphisms in genes in vascular endothelial pathways.We genotyped study participants for 23 single nucleotide polymorphisms (SNPs) in endothelin 1 (EDN1), nitric oxide synthase 3, and E selectin (SELE). We tested 17 of these SNPs for associations with BP response to potassium supplementation in 1843 participants. Association tests used population-based [generalized estimation equation (GEE)] and family-based (quantitative transmission disequilibrium test) methods, as well as tests for gene-by-gene (GxG) interaction (generalized multifactor dimensionalilty reduction and GEE).Single SNP analysis identified significant associations for several SNPs in EDN1 with multiple measures of BP response to potassium supplementation. The cumulative effects of the minor EDN1 alleles that showed significant associations were to reduce measures of BP response by 0.5-0.9 mmHg. We found significant evidence for effects of GxG interactions between EDN1 and SELE, even in the absence of individual associations with SELE variants.Our results implicate variability in EDN1 and SELE as genetic factors that influence BP response to potassium intake. Although such epidemiological studies do not allow direct determination of physiologic mechanisms, our findings of joint effects identify EDN1 and SELE as targets for functional studies to determine their interactions in BP response to potassium intake.

We examined the association between plasma concentrations of high-sensitivity C-reactive protein, soluble intercellular adhesion molecule 1, soluble E-selectin, angiotensin II, renin activity and the risk of hypertension among 2589 study participants aged 20 years and older from Inner Mongolia, China.Three blood pressure measurements were obtained using a standard mercury sphygmomanometer and hypertension was defined as blood pressure of at least 140/90 mmHg or use of antihypertensive medications. Overnight fasting blood samples were obtained to measure the biomarkers of endothelial dysfunction and inflammation.The average levels of high-sensitivity C-reactive protein (7.5 vs. 5.4 mg/l), soluble intercellular adhesion molecule 1 (339.4 vs. 322.6 ng/ml), soluble E-selectin (19.1 vs. 18.2 ng/ml), and angiotensin II (52.0 vs. 47.0 pg/ml) were significantly higher, whereas renin activity (1.3 vs. 1.5 mg/ml.h) was lower in hypertensive compared to normotensive participants (all P value0.001). Compared to the lowest quartile, the multivariable-adjusted odds ratios (95% confidence interval) of hypertension for the highest quartile were 1.41 (1.06, 1.86) for high-sensitivity C-reactive protein, 1.93 (1.48, 2.53) for angiotensin II, and 0.70 (0.54, 0.91) for renin activity.Our study indicated that elevated plasma levels of high-sensitivity C-reactive protein and angiotensin II were positively and renin activity inversely associated with the risk of hypertension. These data suggest that inflammation and endothelial dysfunction may play a role in the cause of hypertension.

Hypertension is a major global-health challenge because of its high prevalence and concomitant risks of cardiovascular disease. We estimated premature deaths attributable to increased blood pressure in China.We did a prospective cohort study in a nationally representative sample of 169,871 Chinese adults aged 40 years and older. Blood pressure and other risk factors were measured at a baseline examination in 1991 and follow-up assessment was done in 1999-2000. Premature death was defined as mortality before age 72 years in men and 75 years in women, which were the average life expectancies in China in 2005. We calculated the numbers of total and premature deaths attributable to blood pressure using population-attributable risk, mortality, and the population size of China in 2005.Hypertension and prehypertension were significantly associated with increased all-cause and cardiovascular mortality (p0.0001). We estimated that in 2005, 2.33 million (95% CI 2.21-2.45) cardiovascular deaths were attributable to increased blood pressure in China: 2.11 million (2.03-2.20) in adults with hypertension and 0.22 million (0.19-0.25) in adults with prehypertension. Additionally, 1.27 million (1.18-1.36) premature cardiovascular deaths were attributable to raised blood pressure in China: 1.15 million (1.08-1.22) in adults with hypertension and 0.12 million (0.10-0.14) in adults with prehypertension. Most blood pressure-related deaths were caused by cerebrovascular diseases: 1.86 million (1.76-1.96) total deaths and 1.08 million (1.00-1.15) premature deaths.Increased blood pressure is the leading preventable risk factor for premature mortality in the Chinese general population. Prevention and control of this condition should receive top public-health priority in China.American Heart Association (USA); National Heart, Lung, and Blood Institute, National Institutes of Health (USA); Ministry of Health (China); and Ministry of Science and Technology (China).

OBJECTIVE: To examine the excess risks associated with prehypertension and absolute benefit of treatment. METHODS: We conducted a prospective cohort study in 169 871 Chinese adults aged 40 years and older. Data on blood pressure and covariables were obtained at a baseline examination in 1991 and follow-up evaluation was conducted in 1999-2000. RESULTS: Compared with normotension (

Since insulin resistance is thought to be the underlying mechanism for metabolic syndrome, affected individuals might be sensitive to a dietary sodium intervention. We aimed to examine the association between metabolic syndrome and salt sensitivity of blood pressure.1906 Chinese participants without diabetes, aged 16 years or more, were selected to receive a low-sodium diet (51.3 mmol per day) for 7 days followed by a high-sodium diet (307.8 mmol per day) for an additional 7 days. Participants were excluded from the analysis if metabolic risk factor information was missing or if they did not complete their dietary interventions. Blood pressure was measured at baseline and on days 2, 5, 6, and 7 of each intervention. Metabolic syndrome was defined as the presence of three or more of: abdominal obesity, raised blood pressure, high triglyceride concentration, low HDL cholesterol, or high glucose. High salt sensitivity was defined as a decrease in mean arterial blood pressure of more than 5 mm Hg during low-sodium or an increase of more than 5 mm Hg during high-sodium intervention. This study is registered with ClinicalTrials.gov, number NCT00721721.Of the 1881 participants with information regarding metabolic syndrome, 283 had metabolic syndrome. 1853 participants completed the low-sodium diet and 1845 completed the high-sodium diet. Multivariable-adjusted mean changes in blood pressure were significantly greater in participants with metabolic syndrome than in those without on both low-sodium and high-sodium diets (p0.0001 for all comparisons). Additionally, risk of salt sensitivity rose with increasing numbers of risk factors for metabolic syndrome. Compared with those with no risk factors, participants with four or five had a 3.54-fold increased odds (95% CI 2.05-6.11) of high salt-sensitivity during the low-sodium and a 3.13-fold increased odds (1.80-5.43) of high salt-sensitivity during the high-sodium intervention.These results suggest that metabolic syndrome enhances blood pressure response to sodium intake. Reduction in sodium intake could be an especially important component in reducing blood pressure in patients with multiple risk factors for metabolic syndrome.

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.

To examine the association between blood pressure (BP) and mortality among patients with a history of cardiovascular disease (CVD) in China.We conducted a prospective cohort study among 4195 CVD patients aged 40 years and older. Data on BP and covariables were obtained at a baseline examination in 1991 and follow-up evaluation was conducted in 1999-2000 using standard protocols.After adjustment for important covariables, a significant and linear relationship was observed between BP level and mortality from CVD and all-causes. For example, compared with those with a systolic BP less than 120 mmHg, patients with a systolic BP of 120-129, 130-139, 140-159, 160-179, and at least 180 mmHg had relative risks (95% confidence interval) of 1.28 (0.92, 1.78), 1.62 (1.19, 2.20), 2.09 (1.58, 2.77), 2.31 (1.73, 3.10), and 2.66 (2.01, 3.53) for CVD mortality, and 1.08 (0.84, 1.38), 1.26 (1.00, 1.60), 1.44 (1.17, 1.79), 1.57 (1.25, 1.96), and 1.86 (1.50, 2.30) for all-cause mortality (both P values0.0001 for linear trends), respectively. The relationship between BP and mortality was slightly stronger for systolic BP compared with diastolic BP or pulse pressure. Lowering BP to a normal level in hypertensive patients could prevent 55.5% of CVD mortality and 31.2% of all-cause mortality among individuals with a history of CVD.These data indicate that there is a strong, independent, and positive association between BP and mortality among patients with a history of CVD. Furthermore, lowering of BP should be an important approach for preventing premature deaths in this population.

Introduction: Hypertension is the leading preventable cause of premature death worldwide. We aimed to examine the global disparities of hypertension prevalence, awareness, treatment, and control in 2010 and compare secular changes in these disparities from 2000 to 2010. Methods: We searched MEDLINE from January 1995 to December 2014 and supplemented with manual searches of references from retrieved articles. A total of 135 population-based studies with 968,419 individuals aged ≥20 years from 90 countries were included. Sex-age-specific prevalences of hypertension from each country were applied to population data to calculate the number of hypertensive adults in each region and globally. Proportions of awareness, treatment, and control from each country were applied to hypertensive populations to obtain regional and global estimates. Results: An estimated 30.2% (95% confidence interval, 30.1-30.4%) of the world’s adult population in 2010 had hypertension; 28.6% (28.3-28.9%) in high-income countries and 30.3% (30.1-30.5%) in low- and middle-income countries. An estimated 1.35 billion (1.34-1.36 billion) people had hypertension in 2010; 349 million (339-359 million) in high-income and 1.00 billion (0.99-1.01 billion) in low- and middle-income countries. From 2000 to 2010, age-standardized prevalence of hypertension decreased by 2.3% in high-income countries but increased by 6.1% in low- and middle-income countries. During the same period, the proportions of awareness (56.6% vs 68.8%), treatment (42.9% vs 56.1%), and control (16.6% vs. 28.9%) increased substantially in high-income countries, whereas awareness (34.7% vs 35.1%), treatment (23.4% vs 26.4%), and control (7.0% vs 7.8%) increased only slightly in low- and middle-income countries. Conclusions: Global disparities in hypertension prevalence, awareness, treatment, and control are large and increasing. Collaborative efforts from national and international stakeholders are urgently needed to combat the emerging hypertension burden in low- and middle-income countries.

BACKGROUND Body mass index (BMI) in childhood predicts obesity in adults, but it is unknown whether rapid increase and variability in BMI during childhood are independent predictors of adult obesity. METHODS The study cohort consisted of 1622 Bogalusa Heart Study participants (aged 20 to 51 years at follow-up) who had been screened at least four times during childhood (aged 4-19 years). BMI rate of change during childhood for each individual was assessed by mixed models; BMI residual standard deviation (RSD) during childhoodwas used as a measure of variability. The average follow-up period was 20.9 years. RESULTS One standard deviation increase in rate of change in BMI during childhood was associated with 1.39 [95% confidence interval (CI): 1.17-1.61] kg/m(2) increase in adult BMI and 2.98 (95% CI: 2.42-3.56) cm increase in adult waist circumference, independently of childhood mean BMI. Similarly, one standard deviation increase in RSD in BMI during childhood was associated with 0.46 (95% CI: 0.23-0.69) kg/m(2) increase in adult BMI and 1.42 (95% CI: 0.82-2.02) cm increase in adult waist circumference. Odds ratio for adult obesity progressively increased from the lowest to the highest quartile of BMI rate of change or RSD during childhood (P for trend

The objective of this study was to assess the association between apolipoprotein E (apoE) genotype and preterm birth (PTB) and small for gestational age (SGA). ApoE phenotyping was performed on 680 women linked to 1065 births. Allele frequencies were compared and PTB and SGA risk was estimated using log-binomial regression. The ɛ2 allele was more common in SGA births (P

Importance Acute ischemic stroke is a leading cause of death and disability worldwide. Several recent clinical trials have shown that endovascular treatment improves clinical outcomes among patients with acute ischemic stroke. Objective To provide an overall and precise estimate of the efficacy of endovascular treatment predominantly using second-generation mechanical thrombectomy devices (stent-retriever devices) compared to medical management on clinical and functional outcomes among patients with acute ischemic stroke. Data Sources MEDLINE, EMBASE, Cochrane Collaboration Central Register of Controlled Clinical Trials, Web of Science, and NIH ClinicalTrials.gov were searched through November 2015. Study Selection Searches returned 3,045 articles. After removal of duplicates, two authors independently screened titles and abstracts to assess eligibility of 2,495 potentially relevant publications. From these, 38 full-text publications were more closely assessed. Finally, 5 randomized controlled trials of endovascular treatment with predominant use of retrievable stents were selected. Data Extraction and Synthesis Three authors independently extracted information on participant and trial characteristics and clinical events using a standardized protocol. Random effects models were used to pool endovascular treatment effects across outcomes. Main Outcomes and Measures The primary outcome was better functional outcome as measured on the modified Rankin Scale at 90 days of follow-up. Secondary outcomes included all-cause mortality and symptomatic intra-cerebral hemorrhage. Results Five trials representing 1,287 patients were included. Overall, patients randomized to endovascular therapy experienced 2.22 times greater odds of better functional outcome compared to those randomized to medical management (95% CI, 1.66 to 2.98; P < 0.0001). Endovascular therapy was not associated with mortality [OR (95% CI), 0.78 (0.54, 1.12); P = 0.1056] or symptomatic intracerebral hemorrhage [OR (95% CI), 1.19 (0.69, 2.05); P = 0.5348]. Meta-regression analysis suggested that shorter times from stroke onset to groin puncture and from stroke onset to reperfusion result in better functional outcomes in ischemic stroke patients (P = 0.0077 and P = 0.0089). There were no significant differences in the beneficial effects of endovascular treatment on functional outcomes across categories of gender, age, stroke severity, ischemic changes on computed tomography, or intravenous tissue plasminogen activator administration. Conclusions and Relevance This meta-analysis demonstrated superior functional outcomes in subjects receiving endovascular treatment compared to medical management. Further, this analysis showed that acute ischemic stroke patients may receive enhanced functional benefit from earlier endovascular treatment.

BACKGROUND The renin-angiotensin-aldosterone system (RAAS) plays an important role in blood pressure (BP) regulation. The current study uses single-marker and gene-based analyses to examine the association between RAAS genes and longitudinal BP phenotypes in a Han Chinese population. METHODS A total of 1,768 participants from the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study were included in the current study. Twenty-seven BP measurements were taken using random-zero sphygmomanometers at baseline and 2 follow-up visits. Mixed-effect models were used to assess the additive associations of 106 single-nucleotide polymorphisms (SNPs) in 10 RAAS genes with longitudinal BP changes and hypertension incidence. Gene-based analyses were conducted using the truncated product method. Attempts were made to replicate significant findings among Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). False discovery rate procedures were used to adjust for multiple testing. RESULTS During an average of 7.2 years of follow-up, average systolic and diastolic BP increased, and 32.1% (512) of participants free from hypertension at baseline developed hypertension. NR3C2 SNPs rs7694064 and rs6856803 were significantly associated with longitudinal changes in systolic BP (P interaction = 6.9×10(-5) and 8.2×10(-4), respectively). Through gene-based analysis, NR3C2 was found to be significantly associated with longitudinal systolic BP change (P value of 1.00×10(-7)), even after removal of significant markers rs7694064 and rs6856803 from the analysis. The association between NR3C2 and longitudinal systolic BP change was replicated in Asian MESA participants (P value of 1.00×10(-4)). CONCLUSIONS These findings indicate that NR3C2 may play an important role in BP progression and development of hypertension.

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: We conducted single-marker, gene-based and pathway-based analyses to examine the association between renin-angiotensin-aldosterone system (RAAS) variants and chronic kidney disease (CKD) progression among Chronic Renal Insufficiency Cohort (CRIC) study participants. Methods: A total of 1,523 white and 1,490 black subjects were genotyped for 490 SNPs in 12 RAAS genes as part of the ITMAT-Broad-CARe array. CKD progression phenotypes included decline in estimated glomerular filtration rate (eGFR) over time and the occurrence of a renal disease event, defined as incident end stage renal disease or halving of eGFR from baseline. Mixed-effects models were used to examine SNP associations with eGFR decline, while Cox proportional hazards models tested SNP associations with renal events. Gene and pathway-based analyses were conducted using the truncated product method. All analyses were stratified by race, and a Bonferroni correction was applied to adjust for multiple testing. Results: Among white and black participants, eGFR declined an average of 1.2 and 2.3 ml/min/1.73m 2 per year, respectively, while renal events occurred in a respective 11.5% and 24.9% of participants. We identified strong gene and pathway-based associations with CKD progression. The AGT and RENBP genes were consistently associated with risk of renal events in separate analyses of white and black participants (all P -6 ). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P -6 ). No single-marker associations with CKD progression were observed. Conclusions: The current study provides strong evidence for a role of the RAAS in CKD progression.

Chronic kidney disease (CKD) is a major risk factor for endstage renal disease, cardiovascular disease, and premature death. Here we estimated the global prevalence and absolute burden of CKD in 2010 by pooling data from population- based studies. We searched MEDLINE (January 1990 to December 2014), International Society of Nephrology Global Outreach Program-funded projects, and bibliographies of retrieved articles and selected 33 studies reporting gender- and age-specific prevalence of CKD in representative population samples. The age-standardized global prevalence of CKD stages 1–5 in adults aged 20 and older was 10.4% in men (95% confidence interval 9.3–11.9%) and 11.8% in women (11.2–12.6%). This consisted of 8.6% in men (7.3–9.8%) and 9.6% in women (7.7–11.1%) in high-income countries, and 10.6% in men (9.4–13.1%) and 12.5% in women (11.8–14.0%) in low- and middle-income countries. The total number of adults with CKD was 225.7 million (205.7–257.4 million) men and 271.8 million (258.0–293.7 million) women. This consisted of 48.3 million (42.3–53.3 million) men and 61.7 million (50.4–69.9 million) women in high-income countries, and 177.4 million (159.2–215.9 million) men and 210.1 million (200.8–231.7 million) women in low- and middle-income countries. Thus, CKD is an important global-health challenge, especially in low- and middle-income countries. National and international efforts for prevention, detection, and treatment of CKD are needed to reduce its morbidity and mortality worldwide.

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.

We examined the associations of common variants in ENaC genes with BP changes and hypertension incidence in a longitudinal family study. A total of 2755 Han Chinese participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) baseline examination were eligible for the current study. The average of nine BP measurements obtained using a random-zero sphygmomanometer at the baseline and each of two follow-up visits were used for the current analysis. The associations of 43 tag-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 BP change according to genotype over time. The false discovery rate (FDR) method was used to adjust for multiple testing. During an average of 7.4 years follow-up, systolic BP (SBP) and diastolic BP (DBP) increased, and approximately 33% of participants developed hypertension. Multiple variants in ENaC genes were significantly associated with longitudinal changes in SBP after adjustment for multiple testing, including SCNN1A SNP rs11064153 ( P interaction = 5.8х10 -4 ; FDR-Q = 0.01); SCNN1G SNPs rs4299163 ( P interaction = 0.011; FDR-Q = 0.05) and rs4401050 ( P interaction = 0.001; FDR-Q = 0.01); and SCNN1B SNP rs1004749 ( P interaction = 0.006; FDR-Q = 0.03). Similar but not significant trends were observed for the associations between both rs11064153 and rs4401050 and DBP changes ( P interaction = 0.024 and 0.005, respectively; FDR-Q = 0.41 and 0.17, respectively) and between rs11604153 and hypertension incidence ( P = 0.017; FDR-Q = 0.19). Our findings indicate that ENaC genes may contribute to longitudinal BP changes in the Han Chinese population. Replication of these findings is warranted.

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.

BackgroundSerum 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 analysis.MethodsA 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.ResultsIn 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 trends were observed for SBP and MAP responses although not significant (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 or gene-based analyses.ConclusionsThe current study identified association of the SGK1 gene and BP salt-sensitivity in the Han Chinese population. Further studies are warranted to identify causal SGK1 gene variants.

Background— Blood pressure (BP) responses to dietary sodium and potassium intervention and cold pressor test vary considerably among individuals. We aimed to identify novel genetic variants influencing individuals’ BP responses to dietary intervention and cold pressor test. Methods and Results— We conducted a genome-wide association study of BP responses in 1881 Han Chinese and de novo genotyped top findings in 698 Han Chinese. Diet-feeding study included a 7-day low-sodium (51.3 mmol/d), a 7-day high-sodium (307.8 mmol/d), and a 7-day high-sodium plus potassium supplementation (60 mmol/d). Nine BP measurements were obtained during baseline observation and each intervention period. The meta-analyses identified 8 novel loci for BP phenotypes, which physically mapped in or near PRMT6 ( P =7.29×10 –9 ), CDCA7 ( P =3.57×10 –8 ), PIBF1 ( P =1.78×10 –9 ), ARL4C ( P =1.86×10 –8 ), IRAK1BP1 ( P =1.44×10 −10 ), SALL1 ( P =7.01×10 –13 ), TRPM8 ( P =2.68×10 –8 ), and FBXL13 ( P =3.74×10 –9 ). There was a strong dose–response relationship between the number of risk alleles of these independent single-nucleotide polymorphisms and the risk of developing hypertension during the 7.5-year follow-up in the study participants. Compared with those in the lowest quartile of risk alleles, odds ratios (95% confidence intervals) for those in the second, third, and fourth quartiles were 1.39 (0.97, 1.99), 1.72 (1.19, 2.47), and 1.84 (1.29, 2.62), respectively ( P =0.0003 for trend). Conclusions— Our study identified 8 novel loci for BP responses to dietary sodium and potassium intervention and cold pressor test. The effect size of these novel loci on BP phenotypes is much larger than those reported by the previously published studies. Furthermore, these variants predict the risk of developing hypertension among individuals with normal BP at baseline.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

BACKGROUND We examined the association between 14 endothelial system genes and salt-sensitivity of blood pressure (BP). METHODS After a 3-day baseline examination, during which time the usual diet was consumed, 1,906 Chinese participants received a 7-day low-sodium diet (51.3 mmol of sodium/day) followed by a 7-day high-sodium diet (307.8 mmol of sodium/day). BP measurements were obtained at baseline and at the end of each intervention using a random-zero sphygmomanometer. RESULTS The DDAH1 rs11161637 variant was associated with reduced BP salt sensitivity, conferring attenuated systolic BP (SBP) and mean arterial pressure (MAP) decreases from baseline to the low-sodium intervention (both P = 2×10(-4)). Examination of genotype-sex interactions revealed that this relation was driven by the strong associations observed in men (P for interactions = 1.10×10(-4) and 0.008, respectively). When switching from the low- to high-sodium intervention, increases in diastolic BP (DBP) and MAP were attenuated by the COL18A1 rs2838944 minor A allele (P = 1.41×10(-4) and 1.55×10(-4), respectively). Conversely, the VWF rs2239153 C variant was associated with increased salt sensitivity, conferring larger DBP and MAP reductions during low-sodium intervention (P = 1.22×10(-4) and 4.44×10(-5), respectively). Ten variants from 3 independent SELE loci displayed significant genotype-sex interactions on DBP and MAP responses to low-sodium (P for interaction = 1.56×10(-3) to 1.00×10(-4)). Among men, minor alleles of 4 correlated markers attenuated BP responses to low-sodium intake, whereas minor alleles of another 4 correlated markers increased BP responses. No associations were observed in women for these variants. Further, qualitative interactions were shown for 2 correlated SELE markers. CONCLUSIONS These data support a role for the endothelial system genes in salt sensitivity.

We examined the association between 799 single-nucleotide polymorphisms in 39 sex hormone genes and blood pressure (BP) responses to a dietary-sodium intervention.A 7-day low-sodium feeding study (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding study (307.8 mmol sodium/day) was conducted among 1,906 Han Chinese participants. Nine BP measurements were obtained at baseline and the end of each intervention period using a random-zero sphygmomanometer.Among men, absolute BP responses to sodium interventions decreased with the number of minor alleles of estrogen receptor 1 (ESR1) markers rs9340844, rs9397453, rs9371562, rs9397459, and rs9383951. For example, mean diastolic blood pressure (DBP) responses to low-sodium intervention (95% confidence interval) were -2.67 (-3.13, -2.22) mm Hg among those with the rs9397453 C/C genotype, -1.23 (-1.98, -0.48) mm Hg among those with the C/T genotype, and 0.08 (-2.31, 2.47) mm Hg among those with the T/T genotype (P = 1×10(-4); false discovery rate (FDR)-q = 0.04). Mean DBP responses to high sodium according to the rs9397453 genotypes were 1.46 (1.03, 1.89) mm Hg among those with C/C, 0.19 (-0.54, 0.91) mm Hg among those with C/T, and -1.10 (-2.82, 0.61) mm Hg among those with T/T (P = 2×10(-4); FDR-q = 0.04). Similar trends were noted for the association between these ESR1 variants and SBP responses to the dietary intervention. There were no significant associations between sex hormone gene variants and salt sensitivity in women, with genotype-gender interactions noted for the ESR1 markers that achieved significance in men.We identified strong, consistent associations between ESR1 gene variants and salt sensitivity in men. Our results support a gender-specific role for ESR1 in the etiology of this complex trait.

An elevated blood pressure (BP) response to the cold pressor test (CPT) is associated with increased risk of hypertension and cardiovascular disease. However, it is still unclear whether BP response to the CPT is a stable and reproducible trait over time. Using the same study protocol, the authors repeated the CPT 4.5 years after initial administration among 568 Han Chinese in rural northern China (2003-2005 and 2008-2009). BP was measured using a standard mercury sphygmomanometer prior to and 0, 1, 2, and 4 minutes after the participants immersed their hand in ice water (3°C-5°C) for 1 minute. Absolute BP levels and BP responses during the CPT in the initial and repeated administrations were highly correlated. For example, the correlation coefficients were 0.67, 0.73, 0.71, and 0.72 for absolute systolic BP levels at 0, 1, 2, and 4 minutes after ice-water immersion (all P 's < 0.0001). The correlation coefficients for systolic BP response were 0.41 at 0 minutes, 0.37 at 1 minute, 0.42 for maximum response, and 0.39 for the area under the curve during CPT (all P 's < 0.0001). These data indicate that BP response to the CPT is a long-term reproducible and stable characteristic in the general population.

The authors conducted a meta-analysis of randomized controlled trials to evaluate the association of dietary protein intake with blood pressure. To identify articles published before April 2011, the authors searched electronic databases, conducted a manual bibliography review, and consulted experts in the field. Forty trials (including 3,277 participants in total) met the eligibility criteria and were included. Using a standardized form, 2 investigators independently abstracted data on study design, participant characteristics, and treatment outcomes. Net change estimates were pooled across trials using random-effects models. Compared with carbohydrate, dietary protein intake was associated with significant changes in mean systolic and diastolic blood pressure of -1.76 mm Hg (95% confidence interval (CI): -2.33, -1.20) and -1.15 mm Hg (95% CI: -1.59, -0.71), respectively (both P 's < 0.001). Both vegetable protein and animal protein were associated with significant blood pressure changes of -2.27 mm Hg (95% CI: -3.36, -1.18) and -2.54 mm Hg (95% CI: -3.55, -1.53), respectively, for systolic blood pressure (both P 's < 0.001) and -1.26 mm Hg (95% CI: -2.26, -0.26) and -0.95 mm Hg (95% CI: -1.72, -0.19), respectively, for diastolic blood pressure (both P 's = 0.014). Blood pressure reduction was not significantly different when vegetable protein was compared directly with animal protein. These findings indicate that partially replacing dietary carbohydrate with protein may be important for the prevention and treatment of hypertension.

High blood pressure (BP) is a complex trait determined by both genetic and environmental factors, as well as the interactions between these factors. Over the past few decades, there has been substantial progress in elucidating the genetic determinants underlying the BP response to sodium intake, or BP salt sensitivity. Research of monogenic BP disorders has highlighted the importance of renal salt handling in BP regulation, implicating genes and biological pathways related to salt sensitivity. Candidate gene studies have contributed important information toward understanding the genomic mechanisms underlying the BP response to salt intake, identifying genes in the renin-angiotensin-aldosterone system, renal sodium channels/transporters, and the endothelial system related to this phenotype. Despite these advancements, genome-wide association studies are still needed to uncover novel mechanisms underlying salt sensitivity, while future sequencing efforts promise the discovery of functional variants related to this complex trait. Delineating the genetic architecture of salt sensitivity will be critical to understanding how genes and dietary sodium interact to influence BP.

High blood pressure (BP) is a complex trait determined by genetic and environmental factors, as well as their interactions. Over the past few decades, there has been substantial progress elucidating the genetic determinants underlying BP response to sodium intake, or BP salt sensitivity. Research of monogenic BP disorders has highlighted the importance of renal salt handling in BP regulation, implicating genes and biological pathways subsequently identified in candidate gene studies of salt sensitivity. Despite these advancements, certain candidate gene findings await replication evidence, and some biological pathways warrant further investigation. Furthermore, results from genome-wide association studies (GWASs) and sequencing work have yet to be reported. GWAS will be valuable for uncovering novel mechanisms underlying salt sensitivity, whereas future sequencing efforts promise the discovery of functional variants related to this complex trait. Delineating the genetic architecture of salt sensitivity will be critical to understanding how genes and dietary sodium interact to influence BP.

The kallikrein-kinin system (KKS) has been implicated in the pathogenesis of salt-sensitive hypertension in animal models. We comprehensively examined the association between genetic variants of the KKS and blood pressure (BP) response to dietary sodium intervention among participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study. A 7-day low-sodium dietary intervention followed by a 7-day high-sodium dietary intervention was carried out among 1,906 GenSalt participants from rural areas of north China. Nine BP measurements were obtained at baseline and on the last three days of each intervention period using a random-zero sphygmomanometer. The percentage changes in mean BP from baseline to low-sodium intervention and from low-sodium to high-sodium intervention were used to assess individual salt-sensitivity. A total of 205 tagSNPs and functional SNPs of eleven genes of the KKS ( BDKRB1 , BDKRB2 , CPN1 , CPN2 , CPM , ECE1 , KLK1 , KLKB1 , KNG1 , MME , SERPINA4 ) were selected and genotyped in this study. Single marker analyses were conducted using the Family Based Association Test program. Genetic variants in the bradykinin receptor B2 ( BDKRB2 ) and endothelin converting enzyme 1 ( ECE1 ) genes showed significant associations with salt sensitivity even after adjusting for multiple testing using the false discovery rate method. SNP rs11847625 of BDKRB2 was significantly associated with systolic BP (SBP) response to low-sodium intervention ( P = 0.0001). Compared to its major allele G, carriers of the minor allele C had greater SBP decrease during low-sodium intervention. Furthermore, a haplotype containing allele C was associated with greater SBP increase to high-sodium intervention ( P = 0.0009). Seven SNPs of ECE1 , one of the degrading enzymes of kinins, were significantly associated with diastolic BP (DBP) response to low-sodium intervention ( P values ranged from 0.0003 to 0.002). Two haplotypes in the linkage disequilibrium block including these seven SNPs were significantly associated with DBP response to low-sodium intervention (P=0.0004 and 0.003, respectively). Our study found that the genetic variants of the KKS were associated with salt sensitivity of BP. Replication and functional studies of the identified variants are warranted in the future.

Lifestyle modifications such as weight loss, increasing physical activity, and reducing alcohol consumption and salt intake have been consistently shown to decrease blood pressure. Less well understood is whether increased dietary protein intake may also reduce blood pressure and the risk of hypertension. We conducted a meta-analysis of randomized controlled trials to assess the hypothesis that increased dietary protein intake decreases systolic and diastolic blood pressure in adults. MEDLINE, EMBASE, Cochrane Library, Web of Science, a registry of soy research trials, bibliography review, and expert consultation were the sources of English and non-English articles published before April 2011. Search terms included randomized controlled trial, blood pressure, dietary proteins, dietary supplements, casein, soy, and meat. Forty randomized controlled trials including 3,277 participants in which amount or source of protein was the only difference between the intervention and comparison groups and that examined blood pressure were included. Using a standardized protocol and data extraction form, two investigators independently abstracted data on study design, participant characteristics, intervention, and treatment outcomes. Net effects of protein on blood pressure were pooled across trials and weighted by the inverse of the variance using random-effects models. Compared to carbohydrate, dietary protein was associated with significant decreases in mean systolic and diastolic blood pressure (95% confidence intervals) of -1.75 (-2.31, -1.19) and -1.16 (-1.60, -0.72) mmHg, respectively (all P

Obesity is a major public health problem in the US population. Low carbohydrate diets are popular as a means of weight loss; however, there is concern for adverse effects on cardiovascular (CV) risk factors. We conducted a meta-analysis of randomized controlled trials comparing the effect of low carbohydrate diets (≤45% of energy from carbohydrates) versus low fat diets (≤30% of energy from fat) on CV risk factors, including systolic and diastolic blood pressure, total cholesterol, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol, triglycerides, body mass index, waist circumference, fasting blood glucose and serum insulin. We searched MEDLINE, EMBASE, Web of Science and the Cochrane Database of Systematic Reviews, and manually examined references in selected articles and relevant literature reviews. Information on participant characteristics, trial design and duration, dietary composition, and CV risk factors were extracted using a standardized protocol. Random effects models were used to pool mean differences between CV risk factors on the two diets. From 785 potentially relevant publications, 23 randomized controlled trials compared low carbohydrate diets with low fat diets with intervention duration ≥ 6 months and reported CV risk factors as primary outcomes. These studies included data from 2,961 participants in total. The average percent of energy from carbohydrate intake was 20.7% on low carbohydrate diets and the average percent of energy from fats was 25.9% on low fat diets. Compared to participants on low fat diets, those on low carbohydrate diets showed favorable changes in HDL cholesterol, triglycerides and body mass index, with pooled net changes (95% CI) of 3.2 mg/dL (1.9, 4.5), -13.0 mg/dL (-17.3, -7.8) and -0.4 kg/m2 (-0.7, -0.1), respectively. After removing studies without intention-to-treat analysis, the change in body mass index was no longer significant (N=16). Changes in total and LDL cholesterol favored low fat diets, but after accounting for publication bias, results were no longer significant for total, LDL and HDL cholesterol. In conclusion, our findings show that low carbohydrate diets were at least as effective as low fat diets for weight loss, and did not have significant adverse effects on other CV risk factors. In fact, low carbohydrate diets had a significant and favorable impact on triglycerides. These findings suggest that low carbohydrate diets can be recommended to obese persons with CV risk factors for the purpose of weight loss.

Previous reports have documented increased blood pressure (BP) salt-sensitivity in women compared to men, suggesting that genes encoding sex hormones could influence BP response to sodium. In the current study, we examined the association between 799 single nucleotide polymorphisms (SNPs) in 44 genes involved in sex hormone biosynthesis, bioavailability and metabolism for their association with BP responses to sodium intervention separately in men and women. A 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding-study (307.8 mmol sodium/day) was conducted among 1,906 participants from 633 Han Chinese families. Nine BP measurements were obtained at baseline and the end of each intervention period using a random-zero sphygmomanometer. Additive associations between each SNP and BP responses to low and high-sodium interventions were assessed using a mixed linear regression model to account for familial dependencies. Among men, absolute BP responses to sodium interventions decreased with the number of minor alleles of estrogen receptor 1 (ESR1) markers rs9340844, rs9397453 and rs9383951. For example, men with genotypes C/C, C/T, and T/T of rs9397453 had respective mean DBP responses [95% confidence intervals (CI)] of: -2.67 (-3.13, -2.22), -1.23 (-1.98, -0.48), and 0.08 (-2.31, 2.47) mmHg to low-sodium intervention [p=1×10 -4 ; false discovery rate (FDR)-q=0.04]; and 1.46 (1.03, 1.89), 0.19 (-0.54, 0.91), and -1.10 (-2.82, 0.61) mmHg to high-sodium intervention (p=2×10 -4 ; FDR-q=0.04). In addition, mean SBP responses (95% CI) were: -5.70 (-6.19, -5.20), -4.34 (-5.37, -3.31), and -2.65 (-5.15, -0.16) mmHg, respectively, for low-sodium intervention (p=2×10 -3 ; FDR-q=0.17); and 4.56 (4.12, 4.99), 3.47 (2.63, 4.30), and 1.97 (-0.49, 4.43) mmHg, respectively, for high-sodium intervention (p=3×10 -3 ; FDR-q=0.40). ESR1 variants were not associated with BP responses in women, with highly significant genotype-gender interactions noted. In summary, we identified strong, consistent associations between genetic variants in the ESR1 gene and decreased salt-sensitivity in men. Although replication of these findings is needed, our results support a role for sex-hormones in the etiology of this complex trait. Funding(This research has received full or partial funding support from the American Heart Association, National Center)

Objective To identify chromosomal regions harboring quantitative trait loci (QTL) for waist circumference (WC) and body mass index (BMI). Design and Methods We conducted a genome-wide linkage scan and regional association study WC and BMI among 633 Chinese families. Results A significant linkage signal for WC was observed at 22q13.31–22q13.33 in the overall analysis (LOD=3.13). Follow-up association study of 22q13.31–13.33 revealed an association between the TBC1D22A gene marker rs16996195 and WC (false discovery rate (FDR)-Q

Background We examined the association of biomarkers of inflammation and endothelial dysfunction with diabetes and metabolic syndrome (MetS) in persons from Inner Mongolia. Methods A cross-sectional study was conducted among 2,536 people aged 20 years and older from Inner Mongolia, China. Overnight fasting blood samples were obtained to measure plasma concentrations of high sensitivity C-reactive protein (hsCRP), soluble inter-cellular adhesion molecule-1 (sICAM-1), sE-selectin, angiotensin II, high density lipoprotein cholesterol, triglycerides, and blood glucose. Waist circumference and blood pressure were measured by trained staff. MetS was defined according to the modified ATP III definition for Asians. Elevated level of the biomarker was defined as values in the upper tertile of the distribution. Participants were categorized into one of four groups based on the presence or absence of metabolic and glycemic abnormalities: 1) free of prediabetes, diabetes and MetS (reference group), 2) prediabetes or diabetes only, 3) MetS without prediabetes or diabetes, and 4) MetS plus prediabetes or diabetes. The multivariable models are adjusted for age, gender, smoking, drinking, family history of hypertension, and body mass index. Results Among study participants, 18.5% had prediabetes, 3.6% had diabetes, and 27.4% of the entire study population had 3 or more components of the MetS. Elevated hsCRP was associated with an increased odds of prediabetes or diabetes only, MetS without prediabetes or diabetes, and MetS plus prediabetes or diabetes with multivariable adjusted odds ratios (95% confidence intervals) of 2.3 (1.7-3.1), 3.0 (2.4-3.8), and 5.8 (4.5-7.5), respectively. Elevated sICAM-1 was associated with increased odds (95% CI) of prediabetes or diabetes only (2.1, 1.6-2.9) and MetS plus prediabetes or diabetes (4.2, 3.2-5.3) but was not associated with MetS alone. Elevated sE-selectin was associated with a modestly increased risk of MetS (OR 1.7, 95% CI 1.4-2.2). Elevated levels of Angiotensin II were not associated with the MetS plus prediabetes or diabetes in this study. Conclusions Diabetes and the MetS are common in the Inner Mongolia population. The biomarkers of inflammation and endothelial dysfunction are associated with increased risk for diabetes and MetS in this population. These results are consistent with results from other populations.

BACKGROUND Blood pressure (BP) homeostasis involves complex interactions among genetic and nongenetic factors, providing major challenges to dissection of the genetic components that influence BP and hypertension. In this study, we examine the effects of interaction of genetic variants with physical activity on BP in a relatively genetically homogenous cohort of rural Chinese villagers. METHODS Generalized estimating equations analysis was used to test for associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with variants in 24 genes in BP pathways (196 single-nucleotide polymorphisms (SNPs)) among 3,142 Chinese participants divided according to physical activity (active vs. inactive groups). RESULTS In the physically active group, two SNPs in NR3C2 were significantly associated with lower SBP, and a SNP in SCNN1B was significantly associated with lower SBP and DBP. In the physically inactive group, a SNP in APLNR was associated with lower SBP, a SNP in GNB3 (guanine nucleotide binding protein, β polypeptide 3) was associated with higher SBP and DBP, and a SNP in BDKRB2 (bradykinin receptor B2) was associated with lower DBP. Cumulative effects in carriers of minor alleles of these SNPs showed reductions of SBP and DBP as large as 8 and 5 mm Hg, respectively, in the active individuals compared to inactive individuals carrying the same number of minor alleles. CONCLUSIONS We found that physical activity modifies the effects of genetic variants on BP. However, our results also show that active individuals with specific genotypes always have lower BP than inactive individuals with the same genotypes, demonstrating the overall beneficial effects of physical activity on BP.

Oral non-absorbable antibiotics work by decreasing intraluminal bacterial content after mechanical bowel preparation. The advantage of adding oral non-absorbable antibiotics to intravenous antibiotics to decrease surgical site infection (SSI) after colorectal surgery is not well known. We conducted a meta-analysis of randomized controlled trials (RCT) comparing the effectiveness of combined oral non-absorbable and intravenous antibiotics versus intravenous antibiotics alone in reducing the incidence of SSI following colorectal surgery.We included RCT comparing a combination of oral non-absorbable antibiotics and intravenous antibiotics to intravenous antibiotics alone in order to prevent SSI after colorectal surgery. Outcomes assessed included postoperative infectious complications, such as surgical wound infections (SWI) defined as a combination of superficial and deep SSI, organ-space infections and anastomotic dehiscence.Sixteen RCT published between 1979 and 2007 were included in the meta-analysis. The overall analyses indicated that patients randomly assigned to an oral non-absorbable antibiotic in addition to an intravenous antibiotic had a reduced risk of SWI (RR: 0.57 [95% CI: 0.43-0.76], p = 0.0002) compared with participants receiving only intravenous antibiotics. The use of oral non-absorbable antibiotics in addition to intravenous antibiotics had no significant effect on organ-space infections (RR: 0.71 [95% CI: 0.43-1.16], p = 0.2) or the risk of anastomotic leak (RR: 0.63 [95% CI: 0.28-1.41], p = 0.3).Our meta-analysis shows that a combination of oral non-absorbable antibiotics and intravenous antibiotics significantly lowers the incidence of SWI compared with intravenous antibiotics alone. In light of our results, the use of oral non-absorbable antibiotics in colorectal surgery should be encouraged.

Background— Rare mutations of the epithelial sodium channel (ENaC) lead to mendelian forms of salt-sensitive hypertension or salt-wasting hypotension. We aimed to examine the association between common variants in the ENaC genes and salt sensitivity of blood pressure (BP). Methods and Results— A total of 1906 Han Chinese participated in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, which includes a 7-day low-sodium intake (51.3 mmol sodium/d) followed by a 7-day high-sodium intake (307.8 mmol sodium/d). Nine BP measurements were obtained at baseline and each intervention period using a random-zero sphygmomanometer. Single-nucleotide polymorphisms, both tagging and functional, from the 3 ENaC subunits, α, β, and γ ( SCNN1A, SCNN1B , and SCNN1G ), were genotyped. Multiple common single-nucleotide polymorphisms in SCNN1G were significantly associated with BP response to low-sodium intervention (rs4073930, P =1.7×10 −5 ; rs4073291, P =1.1×10 −5 ; rs7404408, P =1.9×10 −5 ; rs5735, P =3.0×10 −4 ; rs4299163, P =0.004; and rs4499238, P =0.002) even after correcting for multiple testing. For example, under an additive model, the minor allele G of SNP rs4073291 was associated with 1.33 mm Hg lower systolic BP reduction during low-sodium intervention. Conclusions— This large dietary sodium intervention study indicates that common variants of ENaC subunits may contribute to the variation of BP response to dietary sodium intake. Future studies are warranted to confirm these findings in an independent population and to identify functional variants for salt sensitivity. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00721721.

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OBJECTIVES The purpose of this study was to examine the association between genetic variants in the renin-angiotensin system and blood pressure (BP) responses to the cold pressor test (CPT). METHODS The CPT was conducted among 1998 Han Chinese participants. BP measurements were obtained before and after the CPT using a standard sphygmomanometer according to a standard protocol. The association between SNP genotypes and BP responses to the CPT was assessed using a mixed linear model. RESULTS Of 68 SNPs genotyped in six renin-angiotensin system genes, two were strongly associated with DBP responses to CPT (P ≤ 0.001; false discovery rate q value < 0.05): rs2006765 and rs943580 in the angiotensinogen (AGT) gene. Compared to C allele carriers of rs2006765, the TT homozygotes had a significantly decreased DBP response to the CPT. For participants with the TT genotype, percentage DBP responses were 5.68% (4.25-7.10%), compared to corresponding responses of 9.17% (8.66-9.68%) among participants with the CC+CT genotype. In addition, SNP rs4681443 of the angiotensin type 1 receptor (AGTR1) gene was significantly associated with percentage SBP responses to CPT (P ≤ 0.001; q-value