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.
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.
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).
These findings indicate that NR3C2 may play an important role in BP progression and development of hypertension.
blood pressure; blood pressure changes; genetics; hypertension; rennin–angiotensin–aldosterone system (RAAS).
We conducted single-marker, gene- 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 study participants.
A total of 1523 white and 1490 black subjects were genotyped for 490 single nucleotide polymorphisms (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.
Among white and black participants, eGFR declined an average of 1.2 and 2.3 mL/min/1.73 m2/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 (both P < 1.00 × 10−6). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P < 1.00 × 10−6). No single-marker associations with CKD progression were observed.
The current study provides strong evidence for a role of the RAAS in CKD progression.
chronic kidney disease; genetics; renin–angiotensin–aldosterone system
We used single-marker and novel gene-based methods to examine the associations of endothelial system genes with blood pressure (BP) changes and hypertension in a longitudinal family study.
The Genetic Epidemiology Network of Salt Sensitivity follow-up study was conducted among 1,768 Chinese participants from 633 families. Nine BP measurements were obtained at baseline and at 2 follow-up visits using a random-zero sphygmomanometer. Mixed-effect models were used to assess the additive associations of 206 single-nucleotide polymorphisms (SNPs) in 15 endothelial system genes with longitudinal BP changes and hypertension incidence. Gene-based analyses were conducted using the truncated product method. The Bonferroni method was used to adjust for multiple testing in all analyses.
Among those free from hypertension at baseline, 512 (32.1%) developed hypertension during the average 7.2 years of follow-up. In single-marker analyses, each copy of the minor alleles of correlated SELE markers rs4656704, rs6427212, and rs5368 were associated with increased risk of developing hypertension (P
for trend = 1.48×10−4, 6.69×10−5, and 7.64×10−5, respectively). In addition, the minor allele of SELE marker rs3917436 was associated with smaller diastolic BP (DBP) increases over time. Results of gene-based analyses confirmed associations of the SELE gene with the longitudinal BP phenotypes (P values < 1.00×10−6 for DBP change and hypertension incidence). Furthermore, the DDAH1 and COL18A1 genes were associated with systolic BP change (P < 1.00×10−6 and P = 4.00×10−6, respectively), while EDNRA was associated with hypertension incidence (P = 2.39×10−4).
The current study provides strong evidence of a role of endothelial system genes in BP progression and hypertension incidence.
blood pressure changes; common variants; endothelial; hypertension.
We conducted a meta-analysis of randomized controlled trials to examine the association of mobile phone intervention with net change in weight-related measures among overweight and obese adults. We searched electronic databases and conducted a bibliography review to identify articles published between the inception date of each database and March 27, 2014. Fourteen trials (including 1,337 participants in total) that met the eligibility criteria were included. Two investigators independently abstracted information on study characteristics and study outcomes. Net change estimates comparing the intervention group with the control group were pooled across trials using random-effects models. Compared with the control group, mobile phone intervention was associated with significant changes in body weight and body mass index (weight (kg)/height (m)2) of −1.44 kg (95% confidence interval (CI): −2.12, −0.76) and −0.24 units (95% CI: −0.40, −0.08), respectively. Subgroup analyses revealed that the associations were consistent across study-duration and intervention-type subgroups. For example, net body weight changes were −0.92 kg (95% CI: −1.58, −0.25) and −1.85 kg (95% CI: −2.99, −0.71) in trials of shorter (<6 months) and longer (≥6 months) duration, respectively. These findings provide evidence that mobile phone intervention may be a useful tool for promoting weight loss among overweight and obese adults.
behavioral intervention; mobile phones; obesity; overweight; weight loss
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 1,961 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, LOD ≥ 2). A suggestive linkage signal was identified for systolic BP (SBP) response to CPT at 20p13-20p12.3, with a maximum multipoint LOD score of 2.37. Based on regional association analysis with 1,351 SNPs in the linkage region, we found that marker rs2326373 at 20p13 was significantly associated with mean arterial pressure (MAP) responses to CPT (P = 8.8×10−6) after FDR adjustment for multiple comparisons. A similar trend was also observed for SBP response (P = 0.03) and DBP response (P = 4.6×10−5). Results of gene-based analyses showed that variants in genes MCM8 and SLC23A2 were associated with SBP response to CPT (P = 4.0×10−5 and 2.7×10−4, respectively), and variants in genes MCM8 and STK35 were associated with MAP response to CPT (P = 1.5×10−5 and 5.0×10−5, respectively).
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. Further work is warranted to confirm these findings.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov; Unique identifier: NCT00721721.
blood pressure; linkage; genetic association
Hypertension has become a major global health burden due to its high prevalence and associated increase in risk of cardiovascular disease and premature death. It is well established that hypertension is determined by both genetic and environmental factors and their complex interactions. Recent large-scale meta-analyses of genome-wide association studies (GWAS) have successfully identified a total of 38 loci which achieved genome-wide significance (P < 5×10−8) for their association with blood pressure (BP). Although the heritability of BP explained by these loci is very limited, GWAS meta-analyses have elicited renewed optimism in hypertension genomics research, highlighting novel pathways influencing BP and elucidating genetic mechanisms underlying BP regulation. This review summarizes evolving progress in the rapidly moving field of hypertension genetics and highlights several promising approaches for dissecting the remaining heritability of BP. It also discusses the future translation of genetic findings to hypertension treatment and prevention.
Blood pressure; Genetic association studies; Genetic linkage; Genome-wide association study; Hypertension; Rare variants; Sequencing; Risk prediction
We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26,600 East Asian participants (stage-1) followed by replication study of up to 28,783 participants (stage-2). For novel loci, statistical significance was determined by a P<5.0×10−8 in joint analysis of stage-1 and stage-2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of trans-ethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P<1.4×10−3. No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for trans-ethnic replication including rs17249754 at ATP2B1 (P=7.5×10−15), rs2681492 at ATP2B1 (P=3.4×10−7), rs11191593 at NT5C2 (1.1×10−6), rs3824755 at CYP17A1 (P=1.2×10−6), and rs13149993 at FGF5 (P=2.4×10−4). Two additional variants showed suggestive evidence of trans-ethnic replication (consistency in effect direction and P<0.05), including rs319690 at MAP4 (P=0.014) and rs1173771 at NPR3 (P=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 (P=1.2×10−5) and rs11191593 at NT5C2 (P=1.1×10−3), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 (P=6.1×10−3) and rs2681492 at ATP2B1 (P=9.0×10−3). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mmHg for mean arterial pressure and from 0.03 to 0.21 mmHg for pulse pressure. In conclusion, we present the first evidence of trans-ethnic replication of several mean arterial and pulse pressure loci in an East Asian population.
genetics; polymorphism; single nucleotide; blood pressure; hypertension; genome-wide association study; meta-analysis
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.
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<0.05). In gender-stratified analysis, suggestive linkage signals were attained for WC at 2p24.3–2q12.2 and 22q13.33 among females (LOD=2.54 and 2.15, respectively). Among males, 6q12–6q13 was suggestively linked to BMI (LOD= 2.03). Single marker association analyses at these regions identified male-specific relationships of 6 single nucleotide polymorphisms (SNPs) at 2p24.3–2q12.2 (rs100955, rs13020676, rs13014034, rs12990515, rs17024325 and rs2192712) and 5 SNPs at 6q12–6q13 (rs7747318, rs7767301, rs12197115, rs12203049, and rs9454847) with the obesity-related phenotypes (all FDR-Q<0.05). At chromosome 6q12–6q13, markers rs7755450 and rs11758293 predicted BMI in females (both FDR-Q<0.05).
We described genomic regions on chromosomes 2, 6, and 22 which may harbor important obesity-susceptibility loci. Follow-up study of these regions revealed several novel variants associated with obesity related traits. Future work to confirm these promising findings is warranted.
Obesity; genetics; linkage analysis; single nucleotide polymorphisms
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 analysis.
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.
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 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.
The 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.
We examined the association between 14 endothelial system genes and salt-sensitivity of blood pressure (BP).
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.
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.
These data support a role for the endothelial system genes in salt sensitivity.
blood pressure; endothelial system; genes; hypertension; salt sensitivity.
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 (Pdifference = 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.
blood pressure; dietary potassium; family history; hypertension
The purpose of this study was to examine the association between genetic variants in the renin-angiotensin system (RAS) and blood pressure (BP) responses to cold pressor test (CPT).
The CPT was conducted among 1,998 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.
Of 68 SNPs genotyped in 6 RAS genes, two were strongly associated with diastolic BP (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, percent 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 percent SBP responses to CPT (P≤0.001; q-value <0.05).
Briefly, our study identified variants in the AGT and AGTR1 genes that may influence BP responses to CPT in Han Chinese population. These results show that genetic variants in the RAS play an important role in BP responses to CPT, and therefore in predicting future hypertension.
blood pressure; cold pressor test; renin-angiotensin system; genetics; polymorphism
Results from clinical trials examining the effect of intensive glucose control on cardiovascular disease have been conflicting.
To summarize clinical benefits and harms of intensive versus conventional glucose control for adults with type-2 diabetes.
Studies were retrieved by systematically searching the MEDLINE database (January 1950-April 2009) with no language restrictions.
Two independent reviewers screened abstracts or full text articles to identify randomized trials comparing clinical outcomes in type-2 diabetes patients treated with intensive compared to conventional glucose control.
Two investigators independently abstracted data on study variables and outcomes including severe hypoglycemia, cardiovascular disease, and all-cause mortality.
Five trials involving 27,802 adults were included. Intensive glucose targets were lower in the three most recent trials. Summary analyses showed that, compared with conventional control, intensive glucose control reduced the risk of cardiovascular disease (relative risk (RR): 0.90, 95% confidence interval (CI): 0.83, 0.98; risk difference per 1,000 patients per 5 years (RD): -15, CI: -24, -5) but not cardiovascular death (RR: 0.97, CI: 0.76, 1.24; RD: -3, CI: -14, 7) or all-cause mortality (RR: 0.98, CI: 0.84, 1.15; RD: -4, CI: -17, 10) and increased the risk of severe hypoglycemia (RR: 2.03, CI: 1.46, 2.81; RD: 39, CI: 7, 71). Similar to overall analyses, intensive glucose control reduced risk of cardiovascular disease and increased risk of severe hypoglycemia in pooled findings from early and more recent trials.
Summary rather than individual data were pooled across trials.
Intensive glucose control reduced risk for some cardiovascular disease (e.g., non-fatal myocardial infarction), but did not reduce risk for cardiovascular or all-cause mortality and increased risk of severe hypoglycemia.
intensive glucose control; cardiovascular disease; mortality; relative risk; randomized controlled trials; meta-analysis
Genetic factors may influence blood pressure (BP) responses to dietary potassium intake. We examined the association of genetic variants in the apelin-APJ system and angiotensin-converting enzyme 2 (ACE2) with BP responses to potassium supplementation.
We conducted a 7-day potassium supplementation (60 mmol/day) intervention among 1,906 Chinese adults who participated in the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Tag single nucleotide polymorphisms (SNPs) based on HapMap data and potential functional SNPs were selected in the APLN, APLNR, and ACE2 genes. Because the ACE2 and APLN genes are located on the X chromosome, men and women were analyzed separately.
In women, SNP rs2235306 in the APLN gene was significantly associated with diastolic BP (DBP) response to potassium supplementation (P=0.0009). The DBP responses [95% confidence interval (CI)] among those with genotypes T/T, T/C, and C/C were −2.22 (−2.74, −1.70), −1.69 (−2.20, −1.19), and −0.81 (−1.54, −0.09) mmHg, respectively. In men, SNP rs4646174 of the ACE2 gene was significantly associated with systolic BP (SBP), DBP, and mean arterial pressure (MAP) responses to potassium supplementation (P=0.0001, P=0.001, and P=3.0×10−6, respectively). The SBP, DBP and MAP responses (95% CI) were −0.79 (−2.27, 0.69) versus −3.53 (−3.94, −3.12), 1.07 (−0.34, 2.49) versus −1.06 (−1.43, −0.69), and 0.44 (−0.60, 1.48) versus −1.89 (−2.22, −1.55) mmHg among men with minor G allele compared to those with major C allele of rs4646174, respectively.
Our study indicates that genetic variation of APLN and ACE2 may influence BP response to potassium intake.
We examined the association between genetic variants in the apelin system and blood pressure (BP) responses to low- and high-sodium interventions in the GenSalt Study.
A 7-day low-sodium intervention (51.3 mmol sodium/day) followed by a 7-day high-sodium intervention (307.8 mmol sodium/day) was conducted among 1,906 participants from 637 Han Chinese families. BP measurements were obtained at baseline and following each intervention using a random-zero sphygmomanometer. Twenty-three single nucleotide polymorphisms (SNPs), including both tag and functional SNPs, were selected from three candidate genes (APLN, APLNR, and ACE2). Single marker and haplotype analyses were conducted using the FBAT program. The false discovery rate method was used to correct for multiple testing.
SNPs rs2282623 and rs746886 of the APLNR gene were significantly associated with diastolic (DBP) (both P=0.002) and mean arterial pressure (MAP) (P=0.001 and 0.005, respectively) responses to low-sodium intervention. Six SNPs of the ACE2 gene were significantly associated with systolic (SBP), DBP or MAP responses to low-sodium intervention. Three of them, rs1514283, rs1514282, and rs4646176, were also significantly associated with MAP response to high-sodium (all P≤0.006). Haplotype analysis indicated the A-T-T haplotype of APLNR SNPs rs721608-rs2282623-rs746886 was associated with decreased DBP and MAP responses to low-sodium intervention (P=0.001 and 0.003, respectively), while G-C-C was associated with increased SBP and MAP responses to high-sodium intervention (P=0.004 and 0.01, respectively).
This large family-based study indicates that genetic variants in the APLNR and ACE2 genes are significantly associated with BP responses to dietary sodium intervention.
ACE2; apelin; apelin receptor; blood pressure; polymorphism; dietary sodium; salt sensitivity
To examine the association between renin-angiotensin-aldosterone system (RAAS) genes and salt-sensitivity of blood pressure (BP).
A 7-day low-sodium followed by a 7-day high-sodium dietary intervention was conducted among 1,906 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.
Diastolic BP (DBP) and mean arterial pressure (MAP) responses increased with the number of rs4524238 A alleles in the angiotensin II receptor, type 1 (AGTR1) gene. For example, mean DBP responses (95% CI) among those with genotypes G/G, G/A, and A/A were −2.53 (−2.89, −2.18), −3.49 (−4.13, −2.86), and −5.78 (−9.51, −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 (HSD11B2) gene had decreased DBP responses to low-sodium (p-value=0.00004). Those with the C/A and C/C genotypes had DBP responses of −0.70 (−6.62, 5.22) and −2.71 (−4.88, −0.54) mmHg, respectively. X-chromosome renin-binding protein (RENBP) gene markers rs1557501 and rs2269372 were associated with systolic BP (SBP) response to low-sodium in men (p=0.00004 and 0.0001, respectively). SBP responses (95% CI) were −6.13 (−6.68, −5.58) versus −4.07 (−4.88, −3.26) and −6.04 (−6.57, −5.52) versus −3.94 (−4.90, −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.
We identified RAAS variants that were predictive of salt-sensitivity in a Han population with habitually high-sodium intake.
blood pressure; genetics; polymorphism; dietary sodium; salt sensitivity; renin-angiotensin-aldosterone system
We examined the association between twelve single nucleotide polymorphisms (SNPs) in the alpha-adducin (ADD1) and guanine nucleotide binding protein (G protein) beta polypeptide 3 (GNB3) genes and systolic (SBP), diastolic (DBP), and mean arterial (MAP) pressure responses to salt-intake.
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 Han participants from rural north China. BP measurements were obtained at baseline and the end of each intervention period using a random-zero sphygmomanometer.
We identified a significant association between a rare ADD1 variant rs17833172 and SBP, DBP, and MAP responses to high-sodium (p-values<0.0001) and DBP response to low-sodium (p-value=0.002). Participants homozygous for the variant A allele of this marker had SBP, DBP, and MAP responses (95% confidence interval) to high-salt of 1.6 (−1.8, 4.9), −0.8 (−5.6, 4.0), and −0.1 (−4.0, 3.9) mmHg, respectively, versus corresponding responses of 4.6 (2.5, 6.6), 1.7 (−0.2, 3.6), and 2.7 (0.9, 4.4) mmHg, respectively, for those who were heterozygous or homozygous for the G allele. In addition, participants with at least one copy of the A allele of SNP rs1129649 of the GNB3 gene had significantly decreased MAP response to low-salt compared to homozygotes for the C allele (p-value=0.004) with responses of −3.4 (−3.8, −3.0) versus −4.2 (−4.6, −3.8) mmHg, respectively.
These data support a role for the ADD1 and GNB3 genes in BP salt-sensitivity. Future studies aimed at replicating these novel findings are warranted.
blood pressure; genetics; polymorphism; dietary sodium; salt sensitivity; ADD1; GNB3
Blood pressure (BP) homeostasis involves complex interactions among genetic and non-genetic 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.
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 SNPs) among 3,142 Chinese participants divided according to physical activity (active versus inactive groups).
In the physically active group, 2 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 was associated with higher SBP and DBP, and a SNP in BDKRB2 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 mmHg, respectively, in the active individuals compared to inactive individuals carrying the same number of minor alleles.
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 blood pressure.
Blood pressure; Epidemiology; genetics; physical activity; gene by environment interaction
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 1 065 births. Allele frequencies were compared and PTB and SGA risk was estimated using log-binomial regression.
The ε2 allele was more common in SGA births (p < 0.01). SGA risk was increased among ε2 carriers compared to genotype ε3/ε3, though associations were attenuated following adjustment for maternal age, education, race, smoking, and prenatal visits. Stronger associations were observed for term SGA (first birth: aRR = 1.78, 95% CI 1.06 – 2.98; any birth: aRR = 1.52, 95% CI 0.96 – 2.40) and among whites specifically (first: aRR = 2.88, 95% CI 1.45 – 5.69; any: aRR = 2.75, 95% CI 1.46 – 5.22).
Associations between maternal apoE genotype and SGA may represent decreased fetal growth in women with lower circulating cholesterol levels.
Chronic kidney disease (CKD) is a major risk factor for end-stage 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% men (7.3–9.8%) and 9.6% women (7.7–11.1%) in high-income countries, and 10.6% men (9.4–13.1%) and 12.5% 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.
chronic kidney disease; proteinuria
We conducted a genome-wide linkage scan and positional association study to identify genes and variants influencing blood lipid levels among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1906 participants from 633 Han Chinese families. Lipids were measured from overnight fasting blood samples using standard methods. Multipoint quantitative trait genome-wide linkage scans were performed on the high-density lipoprotein, low-density lipoprotein, and log-transformed triglyceride phenotypes. Using dense panels of single nucleotide polymorphisms (SNPs), single-marker and gene-based association analyses were conducted to follow-up on promising linkage signals. Additive associations between each SNP and lipid phenotypes were tested using mixed linear regression models. Gene-based analyses were performed by combining P-values from single-marker analyses within each gene using the truncated product method (TPM). Significant associations were assessed for replication among 777 Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). Bonferroni correction was used to adjust for multiple testing. In the GenSalt study, suggestive linkage signals were identified at 2p11.2–2q12.1 [maximum multipoint LOD score (MML) = 2.18 at 2q11.2] and 11q24.3–11q25 (MML = 2.29 at 11q25) for the log-transformed triglyceride phenotype. Follow-up analyses of these two regions revealed gene-based associations of charged multivesicular body protein 3 (CHMP3), ring finger protein 103 (RNF103), AF4/FMR2 family, member 3 (AFF3), and neurotrimin (NTM ) with triglycerides (P = 4 × 10−4, 1.00 × 10−5, 2.00 × 10−5, and 1.00 × 10−7, respectively). Both the AFF3 and NTM triglyceride associations were replicated among MESA study participants (P = 1.00 × 10−7 and 8.00 × 10−5, respectively). Furthermore, NTM explained the linkage signal on chromosome 11. In conclusion, we identified novel genes associated with lipid phenotypes in linkage regions on chromosomes 2 and 11.
Lipids; Linkage analysis; Positional association analysis; Gene-based analysis
We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
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.
blood pressure; blood pressure changes; epithelial sodium channel (ENaC); hypertension; single nucleotide polymorphisms.
In order to investigate associations of SCNN1A, SCNN1G and SCNN1B genes with blood pressure (BP) in Han Chinese population, we included 2 880 participants did not use antihypertensive medication in the month prior to the baseline survey in the current analysis. Forty-four tag-SNPs in epithelial sodium channel (ENaC) genes were selected and genotyped and nine BP measurements were obtained during 3-day examination. In single-marker analyses, we identified significant associations of SCNN1A marker rs13306613 with diastolic BP (DBP) and SCNN1B marker rs12447134 with systolic BP (SBP) under codominant model after Bonferroni correction (P= 2.82×10−5 and 4.63×10−4, respectively). In addition, 5 SNPs in SCNN1G and 4 SNPs in SCNN1B achieved nominal significance for SBP, DBP or mean arterial pressure (MAP) under the additive model. For example, the minor C allele of rs5735 in SCNN1G gene was associated with decreased SBP, DBP and MAP (P=0.016, 5.41×10−3, and 4.36×10−3, respectively). Gene-based results showed significant associations of SCNN1G and SCNN1Bwith BP levels. This study suggested that ENaC genes play important roles in BP regulation in the Han Chinese population. Future studies are warranted to replicate these findings and functional studies are needed to identify true causal variants in ENaC genes.
epithelial sodium channel; genetic variants; blood pressure; hypertension; GenSalt
Recent studies suggest that central obesity is an important predictor of cardiovascular disease (CVD) in addition to overall obesity. Both inflammation and endothelial dysfunction are associated with increased risk of CVD. We examined the association between body mass index (BMI) and waist circumference (WC) with plasma concentrations of biomarkers of inflammation and endothelial dysfunction.
We conducted a cross-sectional study of 2589 lean, moderately active participants aged 20 years and older in Inner Mongolia, China. Overnight fasting blood samples were obtained to measure the biomarkers including C-reactive protein (CRP), soluble inter-cellular adhesion molecule-1 (sICAM-1), soluble E-selectin (sE-selectin), and angiotensin II. Height, body weight, and WC were measured by trained staff and BMI was calculated (kg/m2).
In univariate analysis, CRP, sICAM-1, and sE-selectin were all significantly higher among individuals with a higher BMI and WC. In multivariate analysis, each standard deviation (SD) increase in WC (9.6 cm) was associated with about 46% higher risk (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.21–1.76) of elevated CRP but a 1 SD increase in BMI (3.5 kg/m2) was not associated with the risk of elevated CRP (OR 0.96, 95% CI 0.80–1.16). However, each SD increase in BMI was associated with about 30% higher risk of having elevated E-selectin (OR 1.30, 95% CI 1.08–1.55).
WC is a stronger predictor of inflammation while BMI is a stronger predictor for endothelial dysfunction. These results suggest measuring both BMI and WC will help to assess the risk of CVD in the Chinese population.
Inflammation; Endothelial dysfunction; C-reactive protein; Body mass index; Waist circumference