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Resequencing Epithelial Sodium Channel Genes Identifies Rare Variants Associated With Blood Pressure Salt-Sensitivity: The GenSalt Study.
Gu, X, Gu, D, He, J, Rao, DC, Hixson, JE, Chen, J, Li, J, Huang, J, Wu, X, Rice, TK, et al
American journal of hypertension. 2018;(2):205-211
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Abstract
BACKGROUND A resequencing study of renal epithelial sodium channel (ENaC) genes was conducted to identify rare variants associated with blood pressure (BP) salt-sensitivity. METHODS The Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study was conducted among 1,906 participants who underwent a 7-day low-sodium followed by a 7-day high-sodium feeding-study. The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study. Three ENaC genes (SCNN1A, SCNN1B, and SCNN1G) were resequenced using capillary-based sequencing methods. Traditional burden tests were utilized to examine association between rare variants and BP salt-sensitivity. Associations of low-frequency and common variants were tested using single-marker analyses. RESULTS Carriers of SCNN1A rare variants had a 0.52 [95% confidence interval (CI): 0.32-0.85] decreased odds of BP salt-sensitivity compared with noncarriers. Neither SCNN1B nor SCNN1G associated with salt-sensitivity of BP in rare variant analyses (P = 0.65 and 0.48, respectively). In single-marker analyses, 3 independent common variants in SCNN1A, rs11614164, rs4764586, and rs3741914, associated with salt-sensitivity after Bonferroni correction (P = 4.4 × 10-4, 1.1 × 10-8, and 1.3 × 10-3). Each copy of the minor allele of rs4764586 was associated with a 1.36-fold (95% CI: 1.23-1.52) increased odds of salt-sensitivity, whereas each copy of the minor allele of rs11614164 and rs3741914 was associated with 0.68-fold (95% CI: 0.55-0.84) and 0.69-fold (95% CI: 0.54-0.86) decreased odds of salt-sensitivity, respectively. CONCLUSIONS This study demonstrated for the first time a relationship between rare variants in the ENaC pathway and BP salt-sensitivity. Future replication and functional studies are needed to confirm the findings in this study. CLINICAL TRIAL REGISTRY Trial Number NCT00721721.
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Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians.
Li, C, Kim, YK, Dorajoo, R, Li, H, Lee, IT, Cheng, CY, He, M, Sheu, WH, Guo, X, Ganesh, SK, et al
Circulation. Cardiovascular genetics. 2017;(2):e001527
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BACKGROUND Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP. METHODS AND RESULTS We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of ≤46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0×10-8 and 2.5×10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03×10-8, stage-2 P=8.64×10-3, joint P=2.63×10-8) and mean arterial pressure (stage-1 P=3.59×10-9, stage-2 P=2.35×10-2, joint P=2.64×10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55×10-6, stage-2 P=1.62×10-5, joint P=3.28×10-9) and mean arterial pressure (stage-1 P=9.19×10-7, stage-2 P=9.69×10-5, joint P=2.15×10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27×10-4 and 3.30×10-4, respectively). CONCLUSIONS We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.
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An association of serum ALT with elevated blood pressure in senior adults: a case-control study.
Hong, X, Wongtongkam, N, Ward, PR, Xiao, S, Wang, S, Peng, Q, Zuo, Q, Zeng, D, Wang, J, Wang, C, et al
Clinical and experimental hypertension (New York, N.Y. : 1993). 2016;(8):691-695
Abstract
Hypertension is a major risk factor for cardiovascular diseases in China; hence, identifying good serum markers might provide cost benefits in terms of reducing morbidity rates. In this population-based case-control study, participants were recruited from five districts in Hunan province, and 416 cases were matched with an equal number of controls. Markers related to elevated blood pressure were assessed: Body Mass Index, total cholesterol, triglycerides, fasting blood glucose, and creatinine. Three potential serum markers homocysteine (HCY), C-reactive protein (CRP), and alanine aminotransferase (ALT) were dichotomized as normal or high level. Binary logistic regression was used to determine odds ratios (ORs) and 95% confidence intervals (CIs). The findings showed that ALT is a powerful serum marker for predicting high risk of high blood pressure with OR = 2.94, 95% CI (1.44-6.02), while there were no significant differences between cases and controls for HCY and CRP. Additionally, it seems likely that high concentrations of HCY conferred a protective effect against elevated blood pressure. When adjusted for sex, ORs for hypertensive females were nearly five times higher than for hypertensive males (OR = 4.34, 95% CI = 1.17-16.04). The study strongly supports findings showing ALT is a potential indicator for patients with hypertension.
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Chronic Kidney Disease Classification in Systolic Blood Pressure Intervention Trial: Comparison Using Modification of Diet in Renal Disease and CKD-Epidemiology Collaboration Definitions.
Rocco, MV, Chapman, A, Chertow, GM, Cohen, D, Chen, J, Cutler, JA, Diamond, MJ, Freedman, BI, Hawfield, A, Judd, E, et al
American journal of nephrology. 2016;(2):130-40
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BACKGROUND Interventional trials have used either the Modification of Diet in Renal Disease (MDRD) or chronic kidney disease (CKD)-Epidemiology Collaboration (CKD-EPI) equation for determination of estimated glomerular filtration rate (eGFR) to define whether participants have stages 3-5 CKD. The equation used to calculate eGFR may influence the number and characteristics of participants designated as having CKD. METHODS We examined the classification of CKD at baseline using both equations in the Systolic Blood Pressure Intervention Trial (SPRINT). eGFR was calculated at baseline using fasting serum creatinine values from a central laboratory. RESULTS Among 9,308 participants with baseline CKD classification using the 4-variable MDRD equation specified in the SPRINT protocol, 681 (7.3%) participants were reclassified to a less advanced CKD stage (higher eGFR) and 346 (3.7%) were reclassified to a more advanced CKD stage (lower eGFR) when the CKD-EPI equation was used to calculate eGFR. For eGFRs <90 ml/min/1.73 m2, participants <75 years were more likely to be reclassified to a less advanced CKD stage; this reclassification was more likely to occur in non-blacks rather than blacks. Participants aged ≥75 years were more likely to be reclassified to a more advanced than a less advanced CKD stage, regardless of baseline CKD stage. Reclassification of baseline CKD status (eGFR <60 ml/min/1.73 m2) occurred in 3% of participants. CONCLUSIONS Use of the MDRD equation led to a higher percentage of participants being classified as having CKD stages 3-4. Younger and non-black participants were more likely to be reclassified as not having CKD using the CKD-EPI equation.
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Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension.
Lu, X, Wang, L, Lin, X, Huang, J, Charles Gu, C, He, M, Shen, H, He, J, Zhu, J, Li, H, et al
Human molecular genetics. 2015;(3):865-74
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Hypertension is a common disorder and the leading risk factor for cardiovascular disease and premature deaths worldwide. Genome-wide association studies (GWASs) in the European population have identified multiple chromosomal regions associated with blood pressure, and the identified loci altogether explain only a small fraction of the variance for blood pressure. The differences in environmental exposures and genetic background between Chinese and European populations might suggest potential different pathways of blood pressure regulation. To identify novel genetic variants affecting blood pressure variation, we conducted a meta-analysis of GWASs of blood pressure and hypertension in 11 816 subjects followed by replication studies including 69 146 additional individuals. We identified genome-wide significant (P < 5.0 × 10(-8)) associations with blood pressure, which included variants at three new loci (CACNA1D, CYP21A2, and MED13L) and a newly discovered variant near SLC4A7. We also replicated 14 previously reported loci, 8 (CASZ1, MOV10, FGF5, CYP17A1, SOX6, ATP2B1, ALDH2, and JAG1) at genome-wide significance, and 6 (FIGN, ULK4, GUCY1A3, HFE, TBX3-TBX5, and TBX3) at a suggestive level of P = 1.81 × 10(-3) to 5.16 × 10(-8). These findings provide new mechanistic insights into the regulation of blood pressure and potential targets for treatments.
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Genome-wide linkage and regional association study of blood pressure response to the cold pressor test in Han Chinese: the genetic epidemiology network of salt sensitivity study.
Yang, X, Gu, D, He, J, Hixson, JE, Rao, DC, Lu, F, Mu, J, Jaquish, CE, Chen, J, Huang, J, et al
Circulation. Cardiovascular genetics. 2014;(4):521-8
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BACKGROUND Blood pressure (BP) response to cold pressor test (CPT) is associated with increased risk of cardiovascular disease. We performed a genome-wide linkage scan and regional association analysis to identify genetic determinants of BP response to CPT. METHODS AND RESULTS A total of 1961 Chinese participants completed the CPT. Multipoint quantitative trait linkage analysis was performed, followed by single-marker and gene-based analyses of variants in promising linkage regions (logarithm of odds ≥2). A suggestive linkage signal was identified for systolic BP response to CPT at 20p13 to 20p12.3, with a maximum multipoint logarithm of odds score of 2.37. On the basis of regional association analysis with 1351 single nucleotide polymorphisms in the linkage region, we found that marker rs2326373 at 20p13 was significantly associated with mean arterial pressure responses to CPT (P=8.8×10(-6)) after false discovery rate adjustment for multiple comparisons. A similar trend was also observed for systolic BP response (P=0.03) and diastolic BP response (P=4.6×10(-5)). Results of gene-based analyses showed that variants in genes MCM8 and SLC23A2 were associated with systolic BP response to CPT (P=4.0×10(-5) and 2.7×10(-4), respectively), and variants in genes MCM8 and STK35 were associated with mean arterial pressure response to CPT (P=1.5×10(-5) and 5.0×10(-5), respectively). CONCLUSIONS Within a suggestive linkage region on chromosome 20, we identified a novel variant associated with BP responses to CPT. We also found gene-based associations of MCM8, SLC23A2, and STK35 in this region. Additional work is warranted to confirm these findings. CLINICAL TRIAL REGISTRATION URL http://www.clinicaltrials.gov; Unique identifier: NCT00721721.
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Maternal history of hypertension and blood pressure response to potassium intake: the GenSalt Study.
Kelly, TN, Gu, D, Rao, DC, Chen, J, Chen, J, Cao, J, Li, J, Lu, F, Ma, J, Mu, J, et al
American journal of epidemiology. 2012;(Suppl 7):S55-63
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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.
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Common variants in epithelial sodium channel genes contribute to salt sensitivity of blood pressure: The GenSalt study.
Zhao, Q, Gu, D, Hixson, JE, Liu, DP, Rao, DC, Jaquish, CE, Kelly, TN, Lu, F, Ma, J, Mu, J, et al
Circulation. Cardiovascular genetics. 2011;(4):375-80
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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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Metabolic syndrome and salt sensitivity of blood pressure in non-diabetic people in China: a dietary intervention study.
Chen, J, Gu, D, Huang, J, Rao, DC, Jaquish, CE, Hixson, JE, Chen, CS, Chen, J, Lu, F, Hu, D, et al
Lancet (London, England). 2009;(9666):829-35
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BACKGROUND 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. METHODS 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. FINDINGS 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 (p<0.0001 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. INTERPRETATION 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.
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Correlation between blood pressure responses to dietary sodium and potassium intervention in a Chinese population.
Zhao, Q, Gu, D, Chen, J, Bazzano, LA, Rao, DC, Hixson, JE, Jaquish, CE, Cao, J, Chen, J, Li, J, et al
American journal of hypertension. 2009;(12):1281-6
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BACKGROUND Blood pressure (BP) responses to dietary sodium and potassium intake vary among individuals. We examined the correlation between BP responses to dietary low-sodium, high-sodium, and potassium supplementation interventions in a feeding study. METHODS A total of 1,906 Chinese aged > or = 16 years participated in the dietary intervention that included a 7-day low-salt intervention (51.3 mmol/day), a 7-day high-salt intervention (307.8 mmol/day), and a 7-day high-salt plus potassium supplementation (60 mmol/day) intervention. BP was measured nine times during the 3-day baseline observation and during the last 3 days of each intervention phase using a random-zero sphygmomanometer. RESULTS The correlation coefficients (95% confidence intervals (CIs)) of the BP responses to low-sodium and high-sodium interventions were -0.47 (-0.51 to -0.44), -0.47 (-0.50 to -0.43), and -0.45 (-0.49 to -0.42) for systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP), respectively (all P < 0.0001). The correlation coefficients (95% CI) of the BP responses to high-sodium intervention and potassium supplementation were -0.52 (-0.56 to -0.49), -0.48 (-0.52 to 0.45), and -0.52 (-0.55 to -0.48) for SBP, DBP, and MAP, respectively (all P < 0.0001). The kappa coefficients were moderate, varying from 0.28 to 0.34, between BP responses to low-sodium and high-sodium interventions (all P < 0.0001). CONCLUSIONS These results indicate there is a moderate correlation between BP responses to low-sodium and to high-sodium interventions, and BP responses to high-sodium intervention and potassium supplementation. Furthermore, our study suggests that individuals who were more sensitive to high-sodium diet might benefit more from a low-sodium and/or high-potassium intervention aimed at lowering BP levels.