Jixiang Ma

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.

Novel Genetic Variants in the α-Adducin and Guanine Nucleotide Binding Protein β-Polypeptide 3 Genes and Salt Sensitivity of Blood Pressure

BACKGROUND We examined the association between 12 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. METHODS 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. Blood pressure (BP) measurements were obtained at baseline and at the end of each intervention period using a random-zero sphygmomanometer. RESULTS 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) mm Hg, respectively, vs. corresponding responses of 4.6 (2.5, 6.6), 1.7 (-0.2, 3.6), and 2.7 (0.9, 4.4) mm Hg, 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) vs. -4.2 (-4.6, -3.8) mm Hg, respectively. CONCLUSIONS 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.

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.

Reproducibility of Blood Pressure Response to the Cold Pressor Test The GenSalt Study

An elevated blood pressure (BP) response to the cold pressor test (CPT) is associated with increased risk of hypertension and cardiovascular disease. However, it is still unclear whether BP response to the CPT is a stable and reproducible trait over time. Using the same study protocol, the authors repeated the CPT 4.5 years after initial administration among 568 Han Chinese in rural northern China (2003-2005 and 2008-2009). BP was measured using a standard mercury sphygmomanometer prior to and 0, 1, 2, and 4 minutes after the participants immersed their hand in ice water (3°C-5°C) for 1 minute. Absolute BP levels and BP responses during the CPT in the initial and repeated administrations were highly correlated. For example, the correlation coefficients were 0.67, 0.73, 0.71, and 0.72 for absolute systolic BP levels at 0, 1, 2, and 4 minutes after ice-water immersion (all P s < 0.0001). The correlation coefficients for systolic BP response were 0.41 at 0 minutes, 0.37 at 1 minute, 0.42 for maximum response, and 0.39 for the area under the curve during CPT (all P s < 0.0001). These data indicate that BP response to the CPT is a long-term reproducible and stable characteristic in the general population.

Analysis of Sex Hormone Genes Reveals Gender Differences in the Genetic Etiology of Blood Pressure Salt Sensitivity: The GenSalt Study

BACKGROUND We examined the association between 799 single-nucleotide polymorphisms in 39 sex hormone genes and blood pressure (BP) responses to a dietary-sodium intervention. METHODS A 7-day low-sodium feeding study (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding study (307.8 mmol sodium/day) was conducted among 1,906 Han Chinese participants. Nine BP measurements were obtained at baseline and the end of each intervention period using a random-zero sphygmomanometer. RESULTS Among men, absolute BP responses to sodium interventions decreased with the number of minor alleles of estrogen receptor 1 (ESR1) markers rs9340844, rs9397453, rs9371562, rs9397459, and rs9383951. For example, mean diastolic blood pressure (DBP) responses to low-sodium intervention (95% confidence interval) were -2.67 (-3.13, -2.22) mm Hg among those with the rs9397453 C/C genotype, -1.23 (-1.98, -0.48) mm Hg among those with the C/T genotype, and 0.08 (-2.31, 2.47) mm Hg among those with the T/T genotype (P = 1×10(-4); false discovery rate (FDR)-q = 0.04). Mean DBP responses to high sodium according to the rs9397453 genotypes were 1.46 (1.03, 1.89) mm Hg among those with C/C, 0.19 (-0.54, 0.91) mm Hg among those with C/T, and -1.10 (-2.82, 0.61) mm Hg among those with T/T (P = 2×10(-4); FDR-q = 0.04). Similar trends were noted for the association between these ESR1 variants and SBP responses to the dietary intervention. There were no significant associations between sex hormone gene variants and salt sensitivity in women, with genotype-gender interactions noted for the ESR1 markers that achieved significance in men. CONCLUSIONS We identified strong, consistent associations between ESR1 gene variants and salt sensitivity in men. Our results support a gender-specific role for ESR1 in the etiology of this complex trait.

Maternal History of Hypertension and Blood Pressure Response to Potassium Intake The GenSalt Study

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.

983 MATERNAL HISTORY OF HYPERTENSION PREDICTS BLOOD PRESSURE RESPONSE TO POTASSIUM INTAKE: THE GENSALT STUDY

Objective: To examine the relationship between parental history of hypertension and blood pressure responses to dietary potassium. Methods: We conducted a dietary-feeding study that included a 7-day high-sodium followed by a 7-day high-sodium plus potassium intervention among 1,871 Chinese participants. Blood pressure was measured on the last 3 days of each intervention phase. Parental hypertension status was ascertained during a baseline examination. Results: Those with a maternal history of hypertension had larger multivariable-adjusted systolic blood pressure responses (95% confidence interval) to potassium intake compared to those with no maternal history: -4.33 (-5.08, -3.57) versus -3.36 (-4.11, -2.62) mmHg, respectively (p-value = 0.003). A consistent trend was observed for diastolic blood pressure responses: -1.81 (-2.45, -1.17) versus -1.35 (-1.98, -0.72), respectively (p-value = 0.08). We noted a stronger association between early-onset maternal hypertension (diagnosed before age 65) and blood pressure responses. Participants with a history of early-onset maternal hypertension compared to those without had systolic blood pressure decreases of -4.74 (-5.64, -3.84) versus -3.54 (-4.26, -2.83) mmHg, respectively (p-value = 0.002) and diastolic blood pressure decreases of -2.25 (-3.01, -1.48) versus -1.38 (-1.99, -0.77) mmHg, respectively (p-value = 0.006). Odds ratios (95% confidence intervals) for high potassium-sensitivity were 1.36 (0.96, 1.93) and 1.62 (1.10, 2.39) for those with a maternal history of hypertension and early-onset hypertension, respectively (p-values = 0.08 and 0.01, respectively). Paternal hypertension was not associated with potassium-sensitivity. Conclusions: Maternal history of hypertension strongly predicted blood pressure responses to potassium intake. Potassium supplementation could be a particularly important strategy for blood pressure reduction among this subgroup of individuals.

421 ANALYSIS OF SEX HORMONE GENES REVEALS GENDER DIFFERENCES IN THE GENETIC ETIOLOGY OF BLOOD PRESSURE SALT-SENSITIVITY: THE GENSALT STUDY

Objective: To examine the association between 799 SNPs in 44 sex hormone genes and BP responses to a dietary-sodium intervention. Methods: A 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding-study (307.8 mmol sodium/day) was conducted among 1,906 Han Chinese participants. Nine BP measurements were obtained at baseline and the end of each intervention period using a random-zero sphygmomanometer. Results: Among men, absolute BP responses to sodium interventions decreased with the number of minor alleles of estrogen receptor 1 (ESR1) markers rs9340844, rs9397453 and rs9383951. For example, men with genotypes C/C, C/T, and T/T of rs9397453 had respective mean DBP responses (95% CI) of: −2.67 (−3.13, −2.22), −1.23 (−1.98, −0.48), and 0.08 (−2.31, 2.47) mmHg to low-sodium intervention (p = 1 × 10−4; false discovery rate (FDR)-q = 0.04); and 1.46 (1.03, 1.89), 0.19 (−0.54, 0.91), and −1.10 (−2.82, 0.61) mmHg to high-sodium intervention (p = 2 × 10−4; FDR-q = 0.04). Mean SBP responses (95% CI) were: −5.70 (−6.19, −5.20), −4.34 (−5.37, −3.31), and −2.65 (−5.15, −0.16) mmHg, respectively, for low-sodium intervention (p = 2 × 10−3; FDR-q = 0.17); and 4.56 (4.12, 4.99), 3.47 (2.63, 4.30), and 1.97 (−0.49, 4.43) mmHg, respectively, for high-sodium intervention (p = 3 × 10−3; FDR-q = 0.40). There were no significant associations between any of the sex hormone gene variants and salt-sensitivity in women, with highly significant genotype-gender interactions noted for ESR1 markers rs9340844, rs9397453, and rs9383951. Conclusions: We identified strong, consistent associations between genetic variants in the ESR1 gene and salt-sensitivity in men. Although replication evidence is needed, our results support a gender-specific role for ESR1 in the etiology of this complex trait.