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Background The role of rare variants in blood pressure (BP) salt-sensitivity is unknown. We conducted a resequencing study of the renin-angiotensin-aldosterone system (RAAS) to identify rare variants associated with BP salt-sensitivity among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Methods The GenSalt study was conducted among 1,906 participants who underwent a 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding study (307.8 mmol sodium/day). The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study. Seven RAAS genes were resequenced using capillary-based sequencing methods. Rare variants were tested for association with BP salt-sensitivity using traditional burden tests. Single-marker analyses were employed to test associations of low-frequency and common variants. Results Aggregate rare variant analysis revealed an association of the RAAS pathway with BP salt-sensitivity. Carriers of rare RAAS variants had a 1.55-fold [95% confidence interval (CI): 1.15, 2.10] higher odds of salt-sensitivity compared to noncarriers (P = 0.004), a finding which was significant after Bonferroni correction. A nominal association of the APLN gene with salt-sensitivity was also identified, with rare APLN variants conferring a 2.22-fold (95% CI: 1.05, 6.58) higher odds of salt-sensitivity (P = 0.03). Single-marker analyses did not identify variant-BP salt-sensitivity associations after Bonferroni adjustment. A nominal association of a low-frequency, missense RENBP variant was identified. Each minor allele of rs78377269 conferred a 2.21-fold (95% CI: 1.10, 4.42) increased odds of salt-sensitivity (P = 0.03). Conclusions This study presents of the first evidence of a contribution of rare RAAS variants to BP salt-sensitivity. Clinical Trial RegistryTrial Number: NCT00721721.

Background Single-marker and novel gene-based methods were employed to examine the associations of the serum/glucocorticoid regulated kinases (SGK) gene family with longitudinal blood pressure (BP) changes and hypertension incidence in a family-based cohort study. Methods Totally, 1,768 Chinese participants from the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study were included in the current analyses. Nine BP measures were obtained at each of 3 visits during the GenSalt follow-up study. Mixed-model and Gene-based analyses were used to examine the associations of the SGK gene family with longitudinal BP phenotypes. Bonferroni correction was applied to account for multiple testing. Results After an average 7.2-year follow-up, 32.2% (513) of participants free of hypertension at baseline developed hypertension. Four novel SNPs in the SGK1 gene were predictive of the longitudinal BP phenotypes. The major alleles of SGK1 rs1763498 and rs114414980 conferred 2.9- and 2.5-fold increased risks of hypertension development, respectively (P = 1.0×10-4 and 6.0×10-4, respectively). In addition, the major allele of SGK1 rs229133 was significantly associated with 0.4mm Hg larger annual increases in systolic BP (P = 4.2×10-4), while the major allele of rs6924468 was significantly associated with 0.2mm Hg smaller annual increases in diastolic BP (P = 4.2×10-4). Gene-based analyses revealed an association of the SGK1 gene with risk of hypertension development (P = 7.4×10-3). No evidence for the SGK2 and SGK3 genes was found. Conclusions The findings of the current study suggest that the SGK1 gene may play a role in long-term BP regulation and hypertension incidence.

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

Hypertension is a major public health challenge worldwide due to its high prevalence and associated increases in risks of cardiovascular diseases.1,2 As the leading risk factor for mortality globally, approximately 13.5% of premature deaths were attributable to high blood pressure (BP) in 2001.2 High BP can be described as a complex trait, influenced by multiple environmental and genetic factors. Heritability studies indicate that about 30%–60% of interindividual variation in BP is genetically determined.3,4 Still, the genomic mechanisms underlying BP regulation remain largely unknown. Several reports have highlighted the importance of the endothelium on relaxing vascular smooth muscle and regulating vasomotor tone.5,6 Such findings suggest a potential role for endothelial dysfunction in the pathogenesis of hypertension. For example, studies have illustrated that endothelial-mediated vasodilatation is reduced not only in animal models of hypertension but also in humans with essential hypertension.7,8 These findings make endothelial system genes attractive candidates for genomic study of BP phenotypes. Several studies have already identified associations between genes encoding components of the endothelial system and prevalent hypertension.9–12 These studies have reported contributions of the endothelial nitric oxide synthase (NOS3), selectin E (SELE), endothelin receptor type A (EDNRA), and endothelin 1 (EDN1) genes to this complex phenotype.9–12 However, genomic research on longitudinal BP phenotypes, such as BP change over time and hypertension incidence, is limited. Only 4 studies of longitudinal BP traits have been conducted,10,13–15 including just 1 study conducted in East Asian participants.15 Furthermore, the previous studies examined only the NOS3 gene with inconsistent results.10,13–15 The paucity of research in this area highlights a need for additional study of the relation between endothelial system genes and longitudinal BP phenotypes. The present study was undertaken to determine whether common variants in endothelial system genes can predict BP changes or hypertension incidence among 1,768 Han Chinese participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study.

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.

BACKGROUND Blood pressure (BP) homeostasis involves complex interactions among genetic and nongenetic 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. METHODS 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 single-nucleotide polymorphisms (SNPs)) among 3,142 Chinese participants divided according to physical activity (active vs. inactive groups). RESULTS In the physically active group, two 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 (guanine nucleotide binding protein, β polypeptide 3) was associated with higher SBP and DBP, and a SNP in BDKRB2 (bradykinin receptor B2) 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 mm Hg, respectively, in the active individuals compared to inactive individuals carrying the same number of minor alleles. CONCLUSIONS 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 BP.

BACKGROUND Genetic determinants of blood pressure (BP) responses to the cold pressor test (CPT), a phenotype associated with risk of hypertension and cardiovascular disease has not been well studied. METHODS We examined the heritability of BP response to CPT in 1,994 subjects from 627 families in rural north China. BP was measured before and at 0, 1, 2, and 4 min after the participants immersed their hand in ice water for 1 min. Heritabilities of baseline BP and responses at 0 min, maximum response, and area-under-the-curve (AUC) during CPT were computed using a variance components method. Additionally, bivariate heritabilities were calculated to test the existence of shared genetic determinants between baseline BP and responses to CPT. RESULTS Heritabilities of baseline BP and responses to CPT were estimated from 14 to 35%, which all significantly differed from 0 (P < or = 0.002). Genetic correlations (s.e.) due to the same genes between baseline BP and responses to CPT ranged from -0.07 (0.14) to 0.21 (0.15), which were not significantly different from 0. Genetic correlations between reactivity and recovery were 0.67 (0.10) and 0.59 (0.10) for systolic (SBP) and diastolic BP (DBP), respectively, which were significantly different from 0. CONCLUSIONS We concluded that (i) baseline BP and BP responses to CPT had strong genetic determinants; (ii) baseline BP and BP response to CPT did not share the same genetic components; and (iii) BP reactivity and recovery shared the same genetic components. These findings may lead to a better understanding of the genetic mechanism of BP responses to CPT.

We examined the relationship between systolic and diastolic blood pressure (BP) and the incidence of cardiovascular disease (CVD) in a nationally representative cohort of 169,871 men and womenor = 40 years of age in China.Data on BP and other variables were obtained at a baseline examination in 1991 using standard protocols. Follow-up evaluation was conducted in 1999-2000, with a response rate of 93.4%.After adjustment for age, sex, cigarette smoking, alcohol consumption, physical activity, body mass index, education, geographic region, urbanization, and time-dependent history of diabetes, a strong and linear association between both systolic and diastolic BP and incidence of CVD, coronary heart disease and stroke were observed (all P0.0001). For example, the relative risks (95% confidence interval (CI)) of CVD incidence were 1.09 (1.00-1.18), 1.25 (1.16-1.35), 1.49 (1.38-1.62), 2.15 (1.99-2.31), 3.01 (2.78-3.27), and 4.16 (3.84-4.51) for those with systolic/diastolic BP of 110-119/75-79, 120-129/80-84, 130-139/85-89, 140-159/90-99, 160-179/100-109, andor = 180/110 mm Hg compared to those with BP110/75 mm Hg. Increases in systolic BP were associated with a greater risk of CVD compared to corresponding increases in diastolic BP. The linear trend for increased CVD risk being related to higher BP levels was observed in all subgroups of gender, age, body weight, and cigarette smoking.Our results indicate that there is a strong, linear, and independent relationship between BP levels and the risk of CVD in Chinese adults. Systolic BP is a stronger predictor of CVD risk compared to diastolic BP.