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Context: Racial disparities in advance care planning (ACP) have been consistently identified in the literature. Few interventions have been designed to address the disparities identified., Objectives: To assess the feasibility, acceptability, and preliminary efficacy of a culturally sensitive, pilot ACP intervention for African American patients diagnosed with cancer in a safety net healthcare system., Methods: Eligible patients with stage II, III, or IV breast, lung, colorectal, or prostate cancer were identified from the electronic health record, recruited, and randomized to the intervention group or usual care control group. Intervention participants met with an African American lay health advisor who assisted them in watching a video that addressed completion of ACP and facilitated ACP discussion. Descriptive analyses were conducted to examine baseline sociodemographic and clinical characteristics, cancer health literacy, and religious coping among participants. Logistic regression analyses were conducted to evaluate predictors of positive change in stage of intent to discuss ACP at 1, 3, and 6-months post intervention., Results: Seventy-six participants were recruited and randomized (38 intervention, 38 controls). The mean age for participants was 58.8 years (SD 10.8), 62.5% were female, and 90.2% had stage III or IV disease. The intervention proved feasible with 89.5% completion. Intervention participants were more likely to have a positive change in stage of intent to discuss a living will or advance directive than usual care controls at one-month (AOR: 4.57, 95%CI: 1.11, 18.82) and 3-months (AOR: 5.38, 95%CI: 1.05, 27.68) post-intervention. The majority (94.1%) of intervention participants would recommend the intervention to a friend or family member., Conclusion: This culturally sensitive ACP program proved to be feasible, acceptable to participants, and showed some promise in promoting discussion about ACP among participants and members of their healthcare team., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( p < 5 × 10 -8 ) and suggestive ( p < 1 × 10 -6 ) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose ( FOXP1, MBOAT4, SKP2, STIM1, STX4 ), brain ( BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A ), and liver ( BRI3, FOXP1 ) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects., Competing Interests: IN is now employed by Celgene. BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. SA is employed by and holds equity in 23andMe, Inc. Authors BK, MW, and CGa were employed by Helmholtz Zentrum München. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 de las Fuentes, Schwander, Brown, Bentley, Winkler, Sung, Munroe, Miller, Aschard, Aslibekyan, Bartz, Bielak, Chai, Cheng, Dorajoo, Feitosa, Guo, Hartwig, Horimoto, Kolčić, Lim, Liu, Manning, Marten, Musani, Noordam, Padmanabhan, Rankinen, Richard, Ridker, Smith, Vojinovic, Zonderman, Alver, Boissel, Christensen, Freedman, Gao, Giulianini, Harris, He, Hsu, Kühnel, Laguzzi, Li, Lyytikäinen, Nolte, Poveda, Rauramaa, Riaz, Robino, Sofer, Takeuchi, Tayo, van der Most, Verweij, Ware, Weiss, Wen, Yanek, Zhan, Amin, Arking, Ballantyne, Boerwinkle, Brody, Broeckel, Campbell, Canouil, Chai, Ida Chen, Chen, Chitrala, Concas, de Faire, de Mutsert, de Silva, de Vries, Do, Faul, Fisher, Floyd, Forrester, Friedlander, Girotto, Gu, Hallmans, Heikkinen, Heng, Homuth, Hunt, Ikram, Jacobs, Kavousi, Khor, Kilpeläinen, Koh, Komulainen, Langefeld, Liang, Liu, Liu, Lohman, Mägi, Manichaikul, McKenzie, Meitinger, Milaneschi, Nauck, Nelson, O’Connell, Palmer, Pereira, Perls, Peters, Polašek, Raitakari, Rice, Rice, Rich, Sabanayagam, Schreiner, Shu, Sidney, Sims, Smith, Starr, Strauch, Tai, Taylor, Tsai, Uitterlinden, van Heemst, Waldenberger, Wang, Wei, Wilson, Xuan, Yao, Yu, Yuan, Zhao, Becker, Bonnefond, Bowden, Cooper, Deary, Divers, Esko, Franks, Froguel, Gieger, Jonas, Kato, Lakka, Leander, Lehtimäki, Magnusson, North, Ntalla, Penninx, Samani, Snieder, Spedicati, van der Harst, Völzke, Wagenknecht, Weir, Wojczynski, Wu, Zheng, Zhu, Bouchard, Chasman, Evans, Fox, Gudnason, Hayward, Horta, Kardia, Krieger, Mook-Kanamori, Peyser, Province, Psaty, Rudan, Sim, Smith, van Dam, van Duijn, Wong, Arnett, Rao, Gauderman, Liu, Morrison, Rotter and Fornage.)

Purpose: Cognitive outcomes in preterm infants may be adversely affected by use of sedation and anesthetic agents. We investigated the associations between anesthetics/sedatives and full-scale intelligence quotient (FSIQ) measured at 36 months corrected age (CA) in very preterm infants (born < 29 weeks gestational age)., Methods: This retrospective cohort study included preterm infants born at < 29 weeks of gestation between 1 January 2006 and 31 December 2012, whose cognitive outcomes were assessed at 36 months CA. Imputed and complete case univariable and adjusted multivariable linear regressions were used to investigate the associations between FSIQ [standardized to mean (standard deviation) 100 (15)] and exposure to volatile anesthetics, propofol, benzodiazepines, barbiturates, and ketamine. These agents were the subject of a 2016 warning from regulatory authorities in the USA recommending caution for administration to children and pregnant women., Results: A total of 731 infants met the inclusion criteria. Unadjusted associations were -7 (95% confidence interval [CI], -10 to -4; P < 0.001) and -6 (95% CI, -10 to -3; P < 0.001) FSIQ points with exposure to warned medications using imputed and complete case analyses, respectively. Imputed and complete case adjusted associations between FSIQ and warned medications were -3 (95% CI, -7 to 0; P = 0.045) and -4 (95% CI, -8 to 0; P = 0.071) FSIQ points, respectively. Adjusted associations between volatile anesthetic exposure only and FSIQ were -3 (95% CI, -6 to 0; P = 0.072) and -5 (95% CI, -9 to -2; P = 0.004) FSIQ points using imputed and complete case data sets, respectively. FSIQ was not associated with opioid exposure., Conclusion: Exposure of very preterm infants to anesthetics/sedatives on the United States Food and Drug Administration warning list was associated with a decrease in FSIQ points at 36 months CA. There was no association between opioid exposure and FSIQ., (© 2022. Canadian Anesthesiologists' Society.)

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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P joint  < 5 × 10 -8 ), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P int  < 5 × 10 -8 ). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P int  = 2 × 10 -6 ). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P int  < 10 -3 ). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10 -8 ). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2019.)

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10 -8 ) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10 -8 ). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2)., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)

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., (© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

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., (© 2017 American Heart Association, Inc.)

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., Competing Interests: Competing Interests: None declared.

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., (© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

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., Competing Interests: Competing Interests: None declared.

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., (© American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways., Competing Interests: Kari Stefansson, Valgerdur Steinthorsdottir, Gudmar Thorleifsson and Unnur Thorsteinsdottir are used by deCODE Genetics/Amgen inc. Gérard Waeber and Peter Vollenweider received an unrestricted grant from GSK to build the CoLaus study. Bruce M. Psaty serves on a DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor).

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.

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., (© 2016 WILEY PERIODICALS, INC.)

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

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., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

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., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

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.

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., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In order to investigate the associations of SCNN1A, SCNN1G and SCNN1B genes with blood pressure (BP) in the Han Chinese population, we included 2880 participants did not use antihypertensive medication in the month prior to the baseline survey in the current analysis. Forty-four tag-single-nucleotide polymorphisms (SNPs) in epithelial sodium channel (ENaC) genes were selected and genotyped, and nine BP measurements were obtained during the 3-day examination. In the single-marker analyses, we identified significant associations of SCNN1A marker rs13306613 with diastolic BP (DBP) and SCNN1B marker rs12447134 with systolic BP (SBP) under codominant model after Bonferroni's correction (P=2.82 × 10(-5) and 4.63 × 10(-4), respectively). In addition, five SNPs in SCNN1G and four SNPs in SCNN1B achieved nominal significance for SBP, DBP or mean arterial pressure (MAP) under the additive model. For example, the minor C allele of rs5735 in SCNN1G gene was associated with decreased SBP, DBP and MAP (P=0.016, 5.41 × 10(-3) and 4.36 × 10(-3), respectively). Gene-based results showed significant associations of SCNN1G and SCNN1B with BP levels. This study suggested that ENaC genes have important roles in BP regulation in the Han Chinese population. Future studies are warranted to replicate these findings, and functional studies are needed to identify true causal variants in ENaC genes.

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Background: We examined the associations of epithelial sodium channel (ENaC) genes with blood pressure (BP) changes and hypertension incidence in a longitudinal family study., Methods: 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., Results: 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))., Conclusions: 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., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© 2014 American Heart Association, Inc.)