Dissemination and implementation research coordination and training to improve cardiovascular health in people living with HIV in sub-Saharan Africa: the research coordinating center of the HLB-SIMPLe Alliance.

As global adoption of antiretroviral therapy extends the lifespan of People Living with HIV (PLHIV) through viral suppression, the risk of comorbid conditions such as hypertension has risen, creating a need for effective, scalable interventions to manage comorbidities in PLHIV. The Heart, Lung, and Blood Co-morbiditieS Implementation Models in People Living with HIV (HLB-SIMPLe) Alliance has been funded by the National Heart, Lung, and Blood Institute (NHLBI) and the Fogarty International Center (FIC) since September 2020. The Alliance was created to conduct late-stage implementation research to contextualize, implement, and evaluate evidence-based strategies to integrate the diagnosis, treatment, and control of cardiovascular diseases, particularly hypertension, in PLHIV in low- and middle-income countries (LMICs).The Alliance consists of six individually-funded clinical trial cooperative agreement research projects based in Botswana, Mozambique, Nigeria, South Africa, Uganda, and Zambia; the Research Coordinating Center; and personnel from NIH, NHLBI, and FIC (the Federal Team). The Federal Team works together with the members of the seven cooperative agreements which comprise the alliance. The Federal Team includes program officials, project scientists, grant management officials and clinical trial specialists. This Alliance of research scientists, trainees, and administrators works collaboratively to provide and support venues for ongoing information sharing within and across the clinical trials, training and capacity building in research methods, publications, data harmonization, and community engagement. The goal is to leverage shared learning to achieve collective success, where the resulting science and training are greater with an Alliance structure rather than what would be expected from isolated and unconnected individual research projects.In this manuscript, we describe how the Research Coordinating Center performs the role of providing organizational efficiencies, scientific technical assistance, research capacity building, operational coordination, and leadership to support research and training activities in this multi-project cooperative research Alliance. We outline challenges and opportunities during the initial phases of coordinating research and training in the HLB-SIMPLe Alliance, including those most relevant to dissemination and implementation researchers.

The HERITAGE Family Study: A Review of the Effects of Exercise Training on Cardiometabolic Health, with Insights into Molecular Transducers.

The aim of the HERITAGE Family Study was to investigate individual differences in response to a standardized endurance exercise program, the role of familial aggregation, and the genetics of response levels of cardiorespiratory fitness and cardiovascular disease and diabetes risk factors. Here we summarize the findings and their potential implications for cardiometabolic health and cardiorespiratory fitness. It begins with overviews of background and planning, recruitment, testing and exercise program protocol, quality control measures, and other relevant organizational issues. A summary of findings is then provided on cardiorespiratory fitness, exercise hemodynamics, insulin and glucose metabolism, lipid and lipoprotein profiles, adiposity and abdominal visceral fat, blood levels of steroids and other hormones, markers of oxidative stress, skeletal muscle morphology and metabolic indicators, and resting metabolic rate. These summaries document the extent of the individual differences in response to a standardized and fully monitored endurance exercise program and document the importance of familial aggregation and heritability level for exercise response traits. Findings from genomic markers, muscle gene expression studies, and proteomic and metabolomics explorations are reviewed, along with lessons learned from a bioinformatics-driven analysis pipeline. The new opportunities being pursued in integrative -omics and physiology have extended considerably the expected life of HERITAGE and are being discussed in relation to the original conceptual model of the study.

Resequencing Epithelial Sodium Channel Genes Identifies Rare Variants Associated With Blood Pressure Salt-Sensitivity: The GenSalt Study.

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.

Genome-Wide Gene-Potassium Interaction Analyses on Blood Pressure: The GenSalt Study (Genetic Epidemiology Network of Salt Sensitivity).

BACKGROUND: Gene-environmental interaction analysis can identify novel genetic factors for blood pressure (BP). We performed genome-wide analyses to identify genomic loci that interact with potassium to influence BP using single-marker (1 and 2 df joint tests) and gene-based tests among Chinese participants of the GenSalt study (Genetic Epidemiology Network of Salt Sensitivity). METHODS AND RESULTS: Among 1876 GenSalt participants, the average of 3 urine samples was used to estimate potassium excretion. Nine BP measurements were taken using a random-zero sphygmomanometer. A total of 2.2 million single nucleotide polymorphisms were imputed using Affymetrix 6.0 genotype data and the Chinese Han of Beijing and Japanese of Tokyo HapMap reference panel. Promising findings (P<1.00×10-4) from GenSalt were evaluated for replication among 775 Chinese participants of the MESA (Multi-ethnic Study of Atherosclerosis). Single nucleotide polymorphism and gene-based results were meta-analyzed across the GenSalt and MESA studies to determine genome-wide significance. The 1 df tests identified interactions for ARL15 rs16882447 on systolic BP (P=2.83×10-9) and RANBP3L rs958929 on pulse pressure (P=1.58×10-8). The 2 df tests confirmed the ARL15 rs16882447 signal for systolic BP (P=1.15×10-9). Genome-wide gene-based analysis identified CC2D2A (P=2.59×10-7) at 4p15.32 and BNC2 (P=4.49×10-10) at 9p22.2 for systolic BP, GGNBP1 (P=1.18×10-8), and LINC00336 (P=1.36×10-8) at 6p21 for diastolic BP, DAB1 (P=1.05×10-13) at 1p32.2, and MIR4466 (P=5.34×10-8) at 6q25.3 for pulse pressure. The BNC2 (P=3.57×10-8) gene was also significant for mean arterial pressure. CONCLUSIONS: We identified 2 novel BP loci and 6 genes through the examination of single nucleotide polymorphism- and gene-based interactions with potassium.

Mentored Training to Increase Diversity among Faculty in the Biomedical Sciences: The NHLBI Summer Institute Programs to Increase Diversity (SIPID) and the Programs to Increase Diversity among Individuals Engaged in Health-related Research (PRIDE).

OBJECTIVE: To report baseline characteristics of junior-level faculty participants in the Summer Institute Programs to Increase Diversity (SIPID) and the Programs to Increase Diversity among individuals engaged in Health-Related Research (PRIDE), which aim to facilitate participants' career development as independent investigators in heart, lung, blood, and sleep research. DESIGN AND SETTING: Junior faculty from groups underrepresented in the biomedical-research workforce attended two, 2-3 week, annual summer research-education programs at one of six sites. Programs provided didactic and/or laboratory courses, workshops to develop research, writing and career-development skills, as well as a mentoring component, with regular contact maintained via phone, email and webinar conferences. Between summer institutes, trainees participated in a short mid-year meeting and an annual scientific meeting. Participants were surveyed during and after SIPID/PRIDE to evaluate program components. PARTICIPANTS: Junior faculty from underrepresented populations across the United States and Puerto Rico participated in one of three SIPID (2007-2010) or six PRIDE programs (2011-2014). RESULTS: Of 204 SIPID/PRIDE participants, 68% were female; 67% African American and 27% Hispanic/Latino; at enrollment, 75% were assistant professors and 15% instructors, with most (96%) on non-tenure track. Fifty-eight percent had research doctorates (PhD, ScD) and 42% had medical (MD, DO) degrees. Mentees' feedback about the program indicated skills development (eg, manuscript and grant writing), access to networking, and mentoring were the most beneficial elements of SIPID and PRIDE programs. Grant awards shifted from primarily mentored research mechanisms to primarily independent investigator awards after training. CONCLUSIONS: Mentees reported their career development benefited from SIPID and PRIDE participation.

Development and Evaluation of Two Abbreviated Questionnaires for Mentoring and Research Self-Efficacy.

OBJECTIVES: To reduce respondent burden for future evaluations of the National Heart, Lung, and Blood Institute-supported Programs to Increase Diversity Among Individuals Engaged in Health-Related Research (PRIDE), a mentored-research education program, we sought to shorten the 33-item Ragins and McFarlin Mentor Role Instrument (RMMRI), measuring mentor-role appraisals, and the 69-item Clinical Research Appraisal Inventory (CRAI), measuring research self-efficacy. METHODS: Three nationally recruited, junior-faculty cohorts attended two, annual 2-3 week Summer Institutes (SI-1/SI-2: 2011/2012, 2012/2013, 2013/2014) at one of six PRIDE sites. Mentees completed the RMMRI two months after mentor assignment and the CRAI at baseline (pre-SI-1) and 6-month (mid-year) and 12-month (post-SI-2) follow-up. Publications data obtained from Scopus in October 2015 were verified with mentees' curriculum vitae. The RMMRI and CRAI were shortened using an iterative process of principal-components analysis. The shortened measures were examined in association with each other (multiple linear regression) and with increase in publications (repeated-measures analysis of covariance). RESULTS: PRIDE enrolled 152 mentees (70% women; 60% Black, 35% Hispanic/Latino). Cronbach's alphas for the new 9-item RMMRI, 19-item CRAI, and four CRAI-19 subscales were excellent. Controlling for baseline self-efficacy and cohort, RMMRI-9 scores were independently, positively associated with post-SI-2 scores on the CRAI-19 and three subscales (writing, study design/data analysis, and collaboration/grant preparation). Controlling for cohort, higher RMMRI-9 and post-SI-2 CRAI-19 scores were each associated with greater increase in publications. CONCLUSIONS: The RMMRI-9 and CRAI-19 retained the excellent psychometric properties of the longer measures. Findings support use of the shortened measures in future evaluations of PRIDE.

Resequencing Study Identifies Rare Renin-Angiotensin-Aldosterone System Variants Associated With Blood Pressure Salt-Sensitivity: The GenSalt Study.

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.

Associations of the Serum/Glucocorticoid Regulated Kinase Genes With BP Changes and Hypertension Incidence: The Gensalt Study.

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.

A Perspective on Promoting Diversity in the Biomedical Research Workforce: The National Heart, Lung, and Blood Institute's PRIDE Program.

Aspiring junior investigators from groups underrepresented in the biomedical sciences face various challenges as they pursue research independence. However, the biomedical research enterprise needs their participation to effectively address critical research issues such as health disparities and health inequities. In this article, we share a research education and mentoring initiative that seeks to address this challenge: Programs to Increase Diversity among Individuals Engaged in Health Related Research (PRIDE), funded by the National Heart, Lung, and Blood Institute (NHLBI). This longitudinal research-education and mentoring program occurs through summer institute programs located at US-based academic institutions. Recruited participants are exposed to didactic and lab-based research-skill enhancement experiences, with year-round mentoring over the course of two years. Mentor-mentee matching is based on shared research interests to promote congruence and to enhance skill acquisition. Program descriptions and sample narratives of participants' perceptions of PRIDE's impact on their career progress are showcased. Additionally, we highlight the overall program design and structure of four of seven funded summer institutes that focus on cardiovascular disease, related conditions, and health disparities. Mentees' testimonials about the value of the PRIDE mentoring approach in facilitating career development are also noted. Meeting the clinical and research needs of an increasingly diverse US population is an issue of national concern. The PRIDE initiative, which focuses on increasing research preparedness and professional development of groups underrepresented in the biomedical research workforce, with an emphasis on mentoring as the critical approach, provides a robust model that is impacting the careers of future investigators.

An Empirical Comparison of Joint and Stratified Frameworks for Studying G × E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group.

Studying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.

Associations Between Genetic Variants of the Natriuretic Peptide System and Blood Pressure Response to Dietary Sodium Intervention: The GenSalt Study.

BACKGROUND: The aim of this study was to comprehensively test the association of genetic variants in the natriuretic peptide (NP) system with blood pressure (BP) response to dietary sodium intervention in a Chinese population. METHODS: We conducted a 7-day low-sodium intervention followed by a 7-day high-sodium intervention among 1,906 participants in rural China. BP measurements were obtained at baseline and each dietary intervention using a random-zero sphygmomanometer. Linear mixed-effect models were used to assess the associations of 48 single-nucleotide polymorphisms (SNPs) in 6 genes of NP system with BP response to dietary sodium intervention. RESULTS: SNP rs5063 in the NPPA gene and SNP rs2077386 in the NPPC gene exhibited significant associations with BP response to low-sodium dietary intervention under recessive genetic model. For rs5063, absolute mean arterial pressure responses (95% confidence interval) to the low-sodium intervention were 1.31 (-1.08, 3.70) mm Hg for TT genotype and -3.74 (-4.01, -3.46) mm Hg for CC or TC genotype, respectively (P = 4.1 × 10(-5)). Individuals with at least one copy of the C allele of rs2077386 had significantly reduction in systolic BP during the low-sodium intervention compared to those with genotype GG with responses of -5.48 (-5.83, -5.14) vs. -2.76 (-3.52, -2.00) mm Hg, respectively (P = 1.9 × 10(-13)). CONCLUSIONS: These novel findings suggested that genetic variants of NP system may contribute to the variation of BP response to sodium intervention in Chinese population. Certainly, replication of these results in other populations and further functional studies are warranted to clarify their role in the regulation of BP and hypertension.

Genomic and transcriptomic predictors of triglyceride response to regular exercise.

AIM: We performed genome-wide and transcriptome-wide profiling to identify genes and single nucleotide polymorphisms (SNPs) associated with the response of triglycerides (TG) to exercise training. METHODS: Plasma TG levels were measured before and after a 20-week endurance training programme in 478 white participants from the HERITAGE Family Study. Illumina HumanCNV370-Quad v3.0 BeadChips were genotyped using the Illumina BeadStation 500GX platform. Affymetrix HG-U133+2 arrays were used to quantitate gene expression levels from baseline muscle biopsies of a subset of participants (N=52). Genome-wide association study (GWAS) analysis was performed using MERLIN, while transcriptomic predictor models were developed using the R-package GALGO. RESULTS: The GWAS results showed that eight SNPs were associated with TG training-response (ΔTG) at p<9.9×10(-6), while another 31 SNPs showed p values <1×10(-4). In multivariate regression models, the top 10 SNPs explained 32.0% of the variance in ΔTG, while conditional heritability analysis showed that four SNPs statistically accounted for all of the heritability of ΔTG. A molecular signature based on the baseline expression of 11 genes predicted 27% of ΔTG in HERITAGE, which was validated in an independent study. A composite SNP score based on the top four SNPs, each from the genomic and transcriptomic analyses, was the strongest predictor of ΔTG (R(2)=0.14, p=3.0×10(-68)). CONCLUSIONS: Our results indicate that skeletal muscle transcript abundance at 11 genes and SNPs at a number of loci contribute to TG response to exercise training. Combining data from genomics and transcriptomics analyses identified a SNP-based gene signature that should be further tested in independent samples.

Aggregate blood pressure responses to serial dietary sodium and potassium intervention: defining responses using independent component analysis.

BACKGROUND: Hypertension is a complex trait that often co-occurs with other conditions such as obesity and is affected by genetic and environmental factors. Aggregate indices such as principal components among these variables and their responses to environmental interventions may represent novel information that is potentially useful for genetic studies. RESULTS: In this study of families participating in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Study, blood pressure (BP) responses to dietary sodium interventions are explored. Independent component analysis (ICA) was applied to 20 variables indexing obesity and BP measured at baseline and during low sodium, high sodium and high sodium plus potassium dietary intervention periods. A "heat map" protocol that classifies subjects based on risk for hypertension is used to interpret the extracted components. ICA and heat map suggest four components best describe the data: (1) systolic hypertension, (2) general hypertension, (3) response to sodium intervention and (4) obesity. The largest heritabilities are for the systolic (64%) and general hypertension (56%) components. There is a pattern of higher heritability for the component response to intervention (40-42%) as compared to those for the traditional intervention responses computed as delta scores (24%-40%). CONCLUSIONS: In summary, the present study provides intermediate phenotypes that are heritable. Using these derived components may prove useful in gene discovery applications.

Blood Pressure Reactivity to the Cold Pressor Test Predicts Hypertension Among Chinese Adults: The GenSalt Study.

BACKGROUND: Blood pressure (BP) hyper-reactivity to the cold pressor test (CPT) has been suggested as a predictor of hypertension. We examined whether BP reactivity to the CPT was associated with hypertension incidence among the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study participants from China. METHODS: A total of 1,961 GenSalt study participants without any antihypertensive treatment completed the CPT at the baseline examination. Hypertension status was assessed at baseline (2003-2005) and 2 follow-up visits (2008-2009 and 2011-2012). RESULTS: After adjustment for multiple covariates, both systolic BP (SBP) and diastolic BP reactivity to the CPT were significantly associated with hypertension incidence. For example, the multivariable adjusted odds ratios (ORs, 95% CI) of developing hypertension were 0.92 (0.66, 1.29), 1.42 (1.03, 1.97), and 1.45 (1.05, 2.00) for participants with maximum SBP responses of 6.7-12.0, 12.1-19.2, and ≥19.3mm Hg, respectively, compared to those with responses of <6.7mm Hg (P for trend = 0.006). Likewise, the multivariable-adjusted ORs (95% CI) of hypertension were 1.12 (0.79, 1.57), 1.62 (1.15, 2.29), and 1.82 (1.30, 2.55) for participants with the area under the curve of SBP responses of 3.0-16.0, 16.1-29.9, and ≥ 30.0mm Hg·min, respectively, compared to those with responses of < 3.0mm Hg·min (P for trend = 0.0001). The associations between BP reactivity variables and the risk of hypertension were not different among subgroups of sex, age, and baseline BP levels. CONCLUSIONS: BP hyperreactivity to the cold stimulus may predict the risk of hypertension among Chinese adults.

Associations of Renin-Angiotensin-Aldosterone System Genes With Blood Pressure Changes and Hypertension Incidence.

BACKGROUND: 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. METHODS: 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. RESULTS: 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)). CONCLUSIONS: These findings indicate that NR3C2 may play an important role in BP progression and development of hypertension.

Associations of Endothelial System Genes With Blood Pressure Changes and Hypertension Incidence: The GenSalt Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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)). CONCLUSIONS: The current study provides strong evidence of a role of endothelial system genes in BP progression and hypertension incidence.

Genome-wide linkage and regional association study of blood pressure response to the cold pressor test in Han Chinese: the genetic epidemiology network of salt sensitivity study.

BACKGROUND: 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 1961 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 ≥2). A suggestive linkage signal was identified for systolic BP response to CPT at 20p13 to 20p12.3, with a maximum multipoint logarithm of odds score of 2.37. On the basis of regional association analysis with 1351 single nucleotide polymorphisms in the linkage region, we found that marker rs2326373 at 20p13 was significantly associated with mean arterial pressure responses to CPT (P=8.8×10(-6)) after false discovery rate adjustment for multiple comparisons. A similar trend was also observed for systolic BP response (P=0.03) and diastolic BP response (P=4.6×10(-5)). Results of gene-based analyses showed that variants in genes MCM8 and SLC23A2 were associated with systolic BP response to CPT (P=4.0×10(-5) and 2.7×10(-4), respectively), and variants in genes MCM8 and STK35 were associated with mean arterial pressure response to CPT (P=1.5×10(-5) and 5.0×10(-5), respectively). CONCLUSIONS: 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. Additional work is warranted to confirm these findings. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov; Unique identifier: NCT00721721.