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 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 individual's BP responses to dietary potassium intake.

Association of genetic variants in the apelin-APJ system and ACE2 with blood pressure responses to potassium supplementation: the GenSalt study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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) mm Hg, 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 x 10(-6), respectively). The SBP, DBP, and MAP responses (95% CI) were -0.79 (-2.27, 0.69) vs. -3.53 (-3.94, -3.12), 1.07 (-0.34, 2.49) vs. -1.06 (-1.43, -0.69), and 0.44 (-0.60, 1.48) vs. -1.89 (-2.22, -1.55) mm Hg among men with minor G allele compared to those with major C allele of rs4646174, respectively. CONCLUSION: Our study indicates that genetic variation of APLN and ACE2 may influence BP response to potassium intake.

Blood pressure response to potassium supplementation is associated with genetic variation in endothelin 1 and interactions with E selectin in rural Chinese.

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

Correlation between blood pressure responses to dietary sodium and potassium intervention in a Chinese population.

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.

Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study.

OBJECTIVE: To examine factors related to blood pressure (BP) responses to dietary sodium and potassium interventions. METHODS: We conducted a dietary feeding study that included a 7-day low-salt intervention (51.3 mmol sodium/day), a 7-day high-salt intervention (307.8 mmol sodium/day), and a 7-day high-salt and potassium-supplementation (60 mmol potassium/day) intervention among 1906 study participants in rural China. The 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 BP responses to low-sodium intervention were significantly greater in women than in men: -8.1 [95% confidence interval (-8.6 to -7.6)] versus -7.0 (-7.5 to -6.6) mmHg for systolic and -4.5 (-4.9 to -4.1) versus -3.4 (-3.8 to -3.0) mmHg for diastolic. Likewise, BP responses to high-sodium interventions were significantly greater in women than in men: 6.4 (5.9-6.8) versus 5.2 (4.8-5.7) mmHg for systolic and 3.1 (2.7-3.5) versus 1.7 (1.4-2.1) mmHg for diastolic (all P < 0.001). In addition, systolic BP responses to sodium interventions increased with age, and both systolic and diastolic BP responses to sodium interventions increased with baseline BP levels. BP responses to potassium supplementation also increased with baseline BP levels. CONCLUSION: These results suggest that female gender, older age, and hypertension increase the sensitivity to dietary sodium intervention. Furthermore, low dietary sodium intake may be more effective in reducing BP among these subgroups.

Association between blood pressure responses to the cold pressor test and dietary sodium intervention in a Chinese population.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Heritability of blood pressure responses to dietary sodium and potassium intake in a Chinese population.

The heritability of blood pressure responses to dietary intervention has not been well studied. We examined the heritability of blood pressure responses to dietary sodium and potassium intake in a family feeding study among 1906 study participants living in rural North China. The dietary intervention included a 7-day low-sodium feeding (51.3 mmol per day), a 7-day high-sodium feeding (307.8 mmol per day), and a 7-day high-sodium plus potassium supplementation (60 mmol per day). Blood pressure was measured 9 times during the 3-day baseline period preceding the intervention and also during the last 3 days of each intervention phase using a random-zero sphygmomanometer. Heritability was computed using maximum likelihood methods under a variance components model as implemented in the computer program SOLAR. The heritabilities of baseline blood pressure were 0.31 for systolic, 0.32 for diastolic, and 0.34 for mean arterial pressure. The heritabilities increased significantly under dietary intervention and were 0.49, 0.49, and 0.51 during low sodium; 0.47, 0.49, and 0.51 during high sodium; and 0.51, 0.52, and 0.53 during potassium supplementation for systolic, diastolic, and mean arterial pressure, respectively. The heritabilities for percentage of blood pressure responses to low sodium were 0.20, 0.21, and 0.23; to high-sodium were 0.22, 0.33, and 0.33; and to potassium supplementation were 0.24, 0.21, and 0.25 for systolic, diastolic, and mean arterial pressure, respectively. Our study indicated that the heritabilities of blood pressure under controlled dietary sodium and potassium intake were significantly higher than those under a usual diet. In addition, the heritabilities of blood pressure responses to dietary sodium and potassium intake were moderate in this study population.