Jianjun Mu

Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease.

We performed a meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases and 5,019 controls followed by replication studies in 15,460 cases and 11,472 controls, all of Chinese Han ancestry. We identify four new loci for coronary artery disease that reached the threshold of genome-wide significance (P < 5 × 10−8). These loci mapped in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2 and ATP2B1. We also replicated four loci previously identified in European populations (in or near PHACTR1, TCF21, CDKN2A-CDKN2B and C12orf51). These findings provide new insights into pathways contributing to the susceptibility for coronary artery disease in the Chinese Han population.

Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension

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.

Genome-Wide Association Study Identifies 8 Novel Loci Associated With Blood Pressure Responses to Interventions in Han Chinese

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.

Genetic variants in the renin-angiotensin-aldosterone system and salt sensitivity of blood pressure.

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.

Common variants in epithelial sodium channel genes contribute to salt sensitivity of blood pressure: The GenSalt study.

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, &agr;, &bgr;, and &ggr; (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.

Reproducibility of Blood Pressure Responses to Dietary Sodium and Potassium Interventions The GenSalt Study

Blood pressure responses to dietary sodium and potassium interventions vary among individuals. We studied the long-term reproducibility of blood pressure responses to dietary sodium and potassium intake. We repeated the dietary sodium and potassium interventions among 487 Chinese adults 4.5 years after the original dietary intervention. The identical dietary intervention protocol, which included a 7-day low-sodium feeding (51.3 mmol/d), a 7-day high-sodium feeding (307.8 mmol/d), and a 7-day high-sodium feeding with oral potassium supplementation (60.0 mmol/d), was applied in both the initial and repeated studies. Three blood pressure measurements were obtained during each of the 3 days of baseline observation and on days 5, 6, and 7 of each intervention period. The results from the 24-hour urinary excretion of sodium and potassium showed excellent compliance with the study diet. Blood pressure responses to dietary intervention in the original and repeated studies were highly correlated. For example, the correlation coefficients (95% confidence interval) for systolic blood pressure levels were 0.77 (0.73–0.80) at baseline, 0.79 (0.75–0.82) during low sodium, 0.80 (0.77–0.83) during high sodium, and 0.82 (0.79–0.85) during high sodium and potassium supplementation interventions (all P<0.0001). The correlation coefficients for systolic blood pressure changes were 0.37 (0.29–0.44) from baseline to low sodium, 0.37 (0.29–0.44) from low to high sodium, and 0.28 (0.20–0.36) from high sodium to high sodium plus potassium supplementation (all P<0.0001). These data indicate that blood pressure responses to dietary sodium and potassium interventions have long-term reproducibility and stable characteristics in the general population.

Family-based randomized trial to detect effects on blood pressure of a salt substitute containing potassium and calcium in hypertensive adolescents.

BACKGROUND Potassium and calcium are important in blood pressure (BP) regulation. The aim of this study was to test the effects on BP of adding potassium and calcium to dietary salt. METHODS A total of 325 adolescents selected with high BP (systolic BP (SBP) >or=90th percentile by age and sex) along with 978 family members. The adolescents were randomized into three groups by coin toss, and their families (300 total) were also allocated to the three groups: one in which 10 mmol of potassium and 10 mmol of calcium were added to the cooking salt, one encouraged to follow a salt-restricted diet, and a control group. In the salt-restricted group, salt intake was decreased gradually through health-behavior education to reach the goal of 50-100 mmol per person per day at 2 years. No intervention took place in for the control group. Salt sensitivity was determined by a volume expansion and contraction protocol at the beginning of the study. The three groups were followed up every 6 months for 2 years. RESULTS At 2 years, systolic and diastolic blood pressure (SBP/DBP) had decreased by 5.9/2.8 mm Hg (4.7/3.6%) in the added-potassium-and-calcium group and by 5.8/1.0 mm Hg (4.8/1.4%) in the salt-restricted group; the values rose in the control group by 1.3/2.3 mm Hg (1.1/1.8%). There was no difference between the added-potassium-and-calcium group and the restricted-salt group (P = 0.24), but both differed significantly from the controls (P < 0.05). Similar changes in BP were found in family members. Subgroup analysis showed that the BP in salt-sensitive (SS) subjects decreased more than in the non-salt-sensitive (NSS) group (P < 0.05). CONCLUSION A salt substitute containing potassium and calcium was as effective as sodium restriction in reducing BP in hypertensive adolescents and their families in a that rural Chinese community.

Impact of High Salt Independent of Blood Pressure on PRMT/ADMA/DDAH Pathway in the Aorta of Dahl Salt-Sensitive Rats

Endothelial dysfunction participates in the development and progression of salt-sensitive hypertension. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). The objectives of this study were to investigate the impact of a high salt diet on the PRMT/ADMA/DDAH (protein arginine methyltransferases; dimethylarginine dimethylaminohydrolase) pathway in Dahl salt-sensitive (DS) rats and SS-13BN consomic (DR) rats, and to explore the mechanisms that regulate ADMA metabolism independent of blood pressure reduction. Plasma levels of nitric oxide (NO) in DS rats given a high salt diet and subjected to intragastric administration of hydralazine (SH + HYD group) were lower than those given a normal salt diet (SN group). There were significant decreases in expression and activity of dimethylarginine dimethylaminohydrolase (DDAH) and endothelial NO synthase (eNOS) in DS rats given a high diet (SH group) in comparison to the SN group. The activity of DDAH and expression of eNOS in the SH + HYD group decreased more significantly than SN group. The mRNA expression of DDAH-1 and DDAH-2 were lowest in the SH group. The results suggest that salt, independent of blood pressure, can affect the PRMT-1/ADMA/DDAH system to a certain degree and lead to endothelial dysfunction in Dahl salt-sensitive rats.

Physical Activity Reduces Salt Sensitivity of Blood Pressure The Genetic Epidemiology Network of Salt Sensitivity Study

Salt sensitivity of blood pressure (BP) is influenced by genetic and environmental factors. A dietary feeding study was conducted from October 2003 to July 2005 that included a 7-day low-sodium intervention (51.3 mmol sodium/day) followed by a 7-day high-sodium intervention (307.8 mmol sodium/day) among 1,906 individuals who were 16 years of age or older and living in rural northern China. Salt sensitivity of BP was defined as mean BP change from the low-sodium intervention to the high-sodium intervention. Usual physical activity during the past 12 months was assessed at baseline using a standard questionnaire. The multivariable-adjusted means of systolic BP responses to high-sodium intervention were 5.21 mm Hg (95% confidence interval (CI): 4.55, 5.88), 4.97 mm Hg (95% CI: 4.35, 5.59), 5.02 mm Hg (95% CI: 4.38, 5.67), and 3.96 mm Hg (95% CI: 3.29, 4.63) among participants from the lowest to the highest quartiles of physical activity, respectively (P = 0.003 for linear trend). The multivariable-adjusted odds ratio of high salt sensitivity of systolic BP was 0.66 (95% CI: 0.49, 0.88) for persons in the highest quartile of physical activity compared with those in the lowest quartile. Physical activity is significantly, independently, and inversely related to salt sensitivity of BP and may be particularly effective in lowering BP among salt-sensitive individuals.

Genetic variants in the renin-angiotensin-aldosterone system and blood pressure responses to potassium intake.

Objective Observational epidemiologic studies and clinical trials have documented that dietary potassium intake lowers blood pressure (BP). We examined the association between genetic variants in the renin–angiotensin–aldosterone system and BP responses to potassium intervention. Methods A 7-day high-sodium followed by a 7-day high-sodium plus 60 mmol/day potassium-supplementation feeding study was conducted among 1906 participants from rural northern China. Nine BP measurements were obtained at each intervention phase using a random-zero sphygmomanometer and 181 single-nucleotide polymorphisms (SNPs) in 11 candidate genes of the renin–angiotensin–aldosterone system were used for analyses. Results Several SNPs in nuclear receptor subfamily 3, group C, member 2 (NR3C2), angiotensin II type 1 receptor (AGTR1), hydroxysteroid (11-beta) dehydrogenase 1 (HSD11B1), and hydroxysteroid (11-beta) dehydrogenase 2 (HSD11B2) genes were significantly associated with BP responses to potassium intervention. For example, the number of G alleles of the N554S missense mutation (rs5527) of NR3C2 was significantly associated with greater SBP responses to potassium intervention; mean [95% confidence interval (CI)] responses (mmHg) were −3.33 (−3.65 to −3.02) for genotype A/A and −5.47 (−6.64 to −4.29) for A/G, respectively (P value = 0.0004). In addition, the number of C alleles of the A1166C variant (rs5186) in AGTR1 was significantly and inversely associated with SBP responses to potassium intervention; mean (95% CI) responses were −3.55 (−3.87 to −3.24) for genotype A/A, −2.45 (−3.27 to −1.62) for A/C, and 3.25 (−5.73 to 12.23) for CC (P value = 0.003). Conclusion These novel findings indicated that genetic variants in the renin–angiotensin–aldosterone system may play an important role in determining an individuals BP responses to dietary potassium intake.