Genome-wide association study identifies 8 novel loci associated with blood pressure responses to interventions in Han Chinese.
ABSTRACT: 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.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).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.
Project description:In the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, we observed that blood pressure (BP) responses to dietary sodium and potassium interventions and the cold pressor test (CPT) varied greatly among individuals. We conducted a replication study to confirm our previous findings among 695 study participants.The dietary intervention included a 7-day low sodium (51.3 mmol/day), a 7-day high sodium (307.8 mmol/day), and a 7-day high sodium with potassium supplementation (307.8 mmol sodium and 60 mmol potassium/day). BP measurements were obtained during the baseline and each intervention phase. During the CPT, BP was measured before and at 0, 1, 2, and 4 minutes after the participants immersed their right hand in ice water for 1 minute.Systolic and diastolic BP responses (mean ± SD (range), mm Hg) were 8.1±8.4 (-39.1 to 18.2) and -3.5±5.1 (-25.1 to 11.1) to low sodium, 9.1±8.4 (-13.3 to 33.1) and 4.0±5.4 (-16.0 to 20.7) to high sodium, and -4.6±5.8 (-31.8 to 11.6) and -1.9±4.3 (-16.9 to 14.2) to potassium supplementation, respectively (all P < 0.0001 for comparison with each former phase). The mean maximum systolic and diastolic BP responses to the CPT were 16.5±10.5 (-15.3 to 63.3) and 7.6±6.1 (-8.7 to 39.3), respectively (all P < 0.0001).Our study indicates that there are large variations in BP responses to dietary sodium and potassium interventions and to the CPT among individuals.
Project description:Blood pressure (BP) responses to the cold pressor test (CPT) and to dietary sodium intake might be related to the risk of hypertension. We examined the association between BP responses to the CPT and to dietary sodium and potassium interventions.The CPT and dietary intervention were conducted among 1906 study participants in rural China. The dietary intervention included three 7-day periods of low sodium intake (3 g/d of salt [sodium chloride] [51.3 mmol/d of sodium]), high sodium intake (18 g/d of salt [307.8 mmol/d of sodium]), and high sodium intake plus potassium chloride supplementation (60 mmol/d). A total of 9 BP measurements were obtained during the 3-day baseline observation and the last 3 days of each intervention using a random-zero sphygmomanometer.Blood pressure response to the CPT was significantly associated with BP changes during the sodium and potassium interventions (all P < .001). Compared with the lowest quartile of BP response to the CPT (quartile 1), systolic BP changes (95% confidence intervals) for the quartiles 2, 3, and 4 were -2.02 (-2.87 to -1.16) mm Hg, -3.17 (-4.05 to -2.28) mm Hg, and -5.98 (-6.89 to -5.08) mm Hg, respectively, during the low-sodium intervention. Corresponding systolic BP changes during the high-sodium intervention were 0.40 (-0.36 to 1.16) mm Hg, 0.44 (-0.35 to 1.22) mm Hg, and 2.30 (1.50 to 3.10) mm Hg, respectively, and during the high-sodium plus potassium supplementation intervention were -0.26 (-0.99 to 0.46) mm Hg, -0.95 (-1.70 to -0.20) mm Hg, and -1.59 (-2.36 to -0.83) mm Hg, respectively.These results indicate that BP response to the CPT was associated with salt sensitivity and potassium sensitivity. Furthermore, a low-sodium or high-potassium diet might be more effective to lower BP among individuals with high responses to the CPT.
Project description:We examined the association between genetic risk score (GRS) for blood pressure (BP), based on single nucleotide polymorphisms identified in previous BP genome-wide association study meta-analyses, and salt and potassium sensitivity of BP among participants of the GenSalt study (Genetic Epidemiology Network of Salt Sensitivity). The GenSalt study was conducted among 1906 participants who underwent a 7-day low-sodium (51.3 mmol sodium/d), 7-day high-sodium (307.8 mmol sodium/d), and 7-day high-sodium plus potassium (60 mmol potassium/d) intervention. BP was measured 9× at baseline and at the end of each intervention period using a random zero sphygmomanometer. Associations between systolic BP (SBP), diastolic BP, and mean arterial pressure GRS and respective SBP, diastolic BP, and mean arterial pressure responses to the dietary interventions were assessed using mixed linear regression models that accounted for familial dependencies and adjusted for age, sex, field center, body mass index, and baseline BP. As expected, baseline SBP, diastolic BP, and mean arterial pressure significantly increased per quartile increase in GRS (P=2.7×10-8, 9.8×10-8, and 6.4×10-6, respectively). In contrast, increasing GRS quartile conferred smaller SBP, diastolic BP, and mean arterial pressure responses to the low-sodium intervention (P=1.4×10-3, 0.02, and 0.06, respectively) and smaller SBP responses to the high-sodium and potassium interventions (P=0.10 and 0.05). In addition, overall findings were similar when examining GRS as a continuous measure. Contrary to our initial hypothesis, we identified an inverse relationship between BP GRS and salt and potassium sensitivity of BP. These data may provide novel implications on the relationship between BP responses to dietary sodium and potassium and hypertension.
Project description:BACKGROUND:To explore how central hemodynamics respond to dietary sodium and potassium interventions, and whether the responses are associated with metabolic traits. METHODS:We conducted a dietary intervention study including a 7-day low-sodium (51.3 mmol sodium/day) intervention, a 7-day high-sodium (307.8 mmol sodium/day) intervention, and a 7-day high-sodium with potassium supplementation (60.0 mmol potassium/day) intervention among 99 northern Chinese subjects aged 18-60 years. Five metabolic traits included abdominal obesity, high triglycerides, low HDL cholesterol, raised blood pressure (BP), and high glucose. Central hemodynamics were measured at baseline and during each intervention. RESULTS:Central systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), and augmentation index (AIx@75) significantly decreased during low-sodium intervention, increased during high-sodium intervention, and then decreased during potassium supplementation. We observed potential linear trends toward significance of central SBP and PP responses to low-sodium intervention, and significant linear trends of responses to high-sodium intervention as the number of metabolic traits grows. For example, among participants with 0 or 1, 2 or 3, and 4 or 5 metabolic traits, central SBP responses to high-sodium intervention were 8.8 [95% confidence interval (5.8, 11.8)], 9.3 (7.1, 11.6), and 14.0 (11.6, 16.3) mmHg, respectively (P for trend = 0.009). Significant linear trends of central SBP and DBP responses to potassium supplementation were also observed. CONCLUSIONS:Central BP and AIx@75 were lowered by sodium reduction and potassium supplementation, and elevated by sodium-loading. The responses of central BP were pronounced among individuals with metabolic traits clustering. CLINICAL TRIALS REGISTRATION:Trial Number NCT00721721 (The current study is registered on ClinicalTrials.gov; https://clinicaltrials.gov).
Project description:Previous studies have shown that genetic factors might have an important role in blood pressure (BP) responses to dietary salt or potassium intake. The aim of this study was to assess the association of common genetic variants of the adiponectin gene with BP responses to controlled dietary sodium or potassium interventions. Subjects (n=334) from 124 families in rural areas of Northern China were recruited. After a 3-day baseline observation, participants sequentially maintained a 7-day low-sodium diet (NaCl, 3?g per day; or sodium, 51.3?mmol per day), followed by a 7-day high-sodium diet (NaCl, 18?g per day; or sodium, 307.8?mmol per day) and a 7-day high-sodium plus potassium supplementation intervention (KCl, 4.5?g per day; or potassium, 60?mmol per day). A total of seven single nucleotide polymorphisms (SNPs) in the adiponectin gene were selected as the study sites. After adjustment for multiple testing, the adiponectin SNP rs16861205 was significantly associated with the diastolic BP (DBP) response to low-salt intervention, and the DBP and mean arterial pressure (MAP) responses to high-salt intervention (P=0.028, 0.023 and 0.027, respectively). SNP rs822394 was associated with the DBP and MAP responses to low-salt intervention and the DBP response to high-salt intervention (P=0.023, 0.030 and 0.033 respectively). Meanwhile, significant association also existed between SNP rs16861194 and the systolic BP response to potassium supplementation intervention (P=0.026). In addition, SNP rs822394 was significantly associated with basal DBP after adjustment for multiple testing (P=0.033). Our study indicated that the genetic polymorphisms in the adiponectin gene are significantly associated with BP responses to dietary sodium and potassium intake.
Project description:The influence of dietary sodium and potassium on blood pressure (BP) has been extensively studied, however their impact on endothelial function, particularly any interactive effects, has received less attention. The purpose of this study was to determine if dietary potassium can offset the deleterious effect of high dietary sodium on endothelial function independent of BP. Thirty-three adults with salt-resistant BP (16 M and 17 F; 27 ± 1 year) completed seven days each of the following diets in a random order: a moderate potassium/low sodium diet (65 mmol potassium/50 mmol sodium; MK/LS), a moderate potassium/high sodium diet (65mmol potassium/300 mmol sodium; MK/HS) and a high potassium/high sodium (120 mmol potassium/300 mmol sodium; HK/HS). On day seven of each diet, 24-h ambulatory BP and a urine collection were performed. Brachial artery flow-mediated dilation (FMD) was measured in response to reactive hyperemia. Between diets, 24-h BP was unchanged confirming salt resistance (p > 0.05). Sodium excretion increased on both HS diets compared to MK/LS (p < 0.05) and potassium excretion was increased on the HK diet compared to MK/LS and MK/HS (p < 0.05) confirming diet compliance. FMD was lower in MK/HS (5.4 ± 0.5%) compared to MK/LS (6.7 ± 0.5%; p < 0.05) and HK/HS (6.4 ± 0.5%), while there was no difference between the MK/LS and HK/HS diets (p > 0.05). These data suggest that dietary potassium provides vascular protection against the deleterious effects of high dietary sodium by restoring conduit artery function.
Project description:Reducing the urinary sodium-to-potassium ratio is important for reducing both blood pressure and risk of cardiovascular disease. Among free-living Japanese individuals, we carried out a randomized trial to clarify the effect of lifestyle modification for lowering urinary sodium-to-potassium ratio using a self-monitoring device.This was an open, prospective, parallel randomized, controlled trial. Ninety-two individuals were recruited from Japanese volunteers. Participants were randomly allocated into intervention and control groups. A month-long dietary intervention on self-monitoring urinary sodium-to-potassium ratio was carried out using monitors (HEU-001F, OMRON Healthcare Co., Ltd., Kyoto, Japan). All participants had brief dietary education and received a leaflet as usual care. Monitors were handed out to the intervention group, but not to the control group. The intervention group was asked to measure at least one spot urine sodium-to-potassium ratio daily, and advised to lower their sodium-to-potassium ratio toward the target of less than 1. Outcomes included changes in 24-hour urinary sodium-to-potassium ratio, sodium excretion, potassium excretion, blood pressure, and body weight in both groups.Mean measurement frequency of monitoring was 2.8 times/day during the intervention. Changes in urinary sodium-to-potassium ratio were -0.55 in the intervention group and -0.06 in the control group (P = 0.088); respective sodium excretion changes were -18.5 mmol/24 hours and -8.7 mmol/24 hours (P = 0.528); and corresponding potassium excretion was 2.6 mmol/24 hours and -1.5 mmol/24 hours (P = 0.300). No significant reductions were observed in either blood pressure or body weight after the intervention.Providing the device to self-monitor a sodium-to-potassium ratio did not achieve the targeted reduction of the ratio in "pure self-management" settings, indicating further needs to study an effective method to enhance the synergetic effect of dietary programs and self-monitoring practice to achieve the reduction. However, we cannot deny the possibility of reducing sodium-to-potassium ratio using a self-monitoring device.
Project description: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.
Project description:Hypertension is the leading cause of death in developed countries and reduction of salt intake is recommended as a key preventive measure.To assess the dietary sodium and potassium intakes in a national sample of Italian children and adolescents and to examine their relationships with BMI and blood pressure (BP) in the framework of the MINISAL survey, a program supported by the Italian Ministry of Health.The study population included 1424 healthy subjects (766 boys, 658 girls) aged 6-18 years (mean age: 10.1±2.9) who were consecutively recruited in participating National Health Service centers in 10 Italian regions. Electrolyte intake was estimated from 24 hour urine collections tested for completeness by the concomitant measurement of creatinine content. Anthropometric indices and BP were measured with standardized procedures.The average estimated sodium intake was 129 mmol (7.4 g of salt) per day among boys and 117 mmol (6.7 g of salt) among girls. Ninety-three percent of the boys and 89% of the girls had a consumption higher than the recommended age-specific standard dietary target. The estimated average daily potassium intakes were 39 mmol (1.53 g) and 36 mmol (1.40 g), respectively, over 96% of the boys and 98% of the girls having a potassium intake lower than the recommended adequate intake. The mean sodium/potassium ratio was similar among boys and girls (3.5 and 3.4, respectively) and over 3-fold greater than the desirable level. Sodium intake was directly related to age, body mass and BP in the whole population.The Italian pediatric population is characterized by excessive sodium and deficient potassium intake. These data suggest that future campaigns should focus on children and adolescents as a major target in the framework of a population strategy of cardiovascular prevention.