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1.
HGG Adv ; 2(1)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-34734193

RESUMO

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A, PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5, CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

2.
JIMD Rep ; 62(1): 74-84, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34765401

RESUMO

Background: Muscle weakness and exercise intolerance contribute to reduced quality of life (QOL) in Barth syndrome (BTHS). Our group previously found that 12 weeks of resistance exercise training (RET) improved muscle strength, however, did not increase muscle (lean) mass or QOL in n = 3 young adults with BTHS. The overall objective of this pilot study was to examine the safety and effectiveness of RET plus daily protein supplementation (RET + protein) on muscle strength, skeletal muscle mass, exercise tolerance, cardiac function, and QOL in late adolescents/young adults with BTHS. Methods: Participants with BTHS (n = 5, age 27 ± 7) performed 12 weeks of supervised RET (60 minutes per session, three sessions/week) and consumed 42 g/day of whey protein. Muscle strength, muscle mass, exercise capacity, cardiac function, and health-related QOL were assessed pre-post intervention. Results: RET + protein was safe, increased muscle strength and quality of life, and tended to increase lean mass. Conclusions: RET + protein appears safe, increases muscle strength and quality of life and tends to increase lean mass. Larger studies are needed to confirm these findings and to fully determine the effects of RET + protein in individuals with BTHS.

3.
Front Digit Health ; 3: 648777, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34713122

RESUMO

Health information technology (HIT) has not been broadly adopted for use in outpatient healthcare settings to effectively address obesity in youth, especially among disadvantaged populations that face greater barriers to good health. A well-designed HIT tool can deliver behavior change recommendations and provide community resources to address this gap, and the Obesity-Related Behavioral Intervention Trials (ORBIT) model can guide its development and refinement. This article reports the application of the ORBIT model to (1) describe the characteristics and design of a novel HIT tool (the PREVENT tool) using behavioral theory, (2) illustrate the use of stakeholder-centered "designing for dissemination and sustainability" principles, and (3) discuss the practical implications and directions for future research. Two types of stakeholder engagement (customer discovery and user testing) were conducted with end users (outpatient healthcare teams). Customer discovery interviews (n = 20) informed PREVENT tool components and intervention targets by identifying (1) what healthcare teams (e.g., physicians, dietitians) identified as their most important "jobs to be done" in helping adolescents who are overweight/obese adopt healthy behaviors, (2) their most critical "pains" and "gains" related to overweight/obesity treatment, and (3) how they define success compared to competing alternatives. Interviews revealed the need for a tool to help healthcare teams efficiently deliver tailored, evidence-based behavior change recommendations, motivate patients, and follow-up with patients within the constraints of clinic schedules and workflows. The PREVENT tool was developed to meet these needs. It facilitates prevention discussions, delivers tailored, evidence-based recommendations for physical activity and food intake, includes an interactive map of community resources to support behavior change, and automates patient follow-up. Based on Self-Determination Theory, the PREVENT tool engages the patient to encourage competence and autonomy to motivate behavior change. The use of this intentional, user-centered design process should increase the likelihood of the intended outcomes (e.g., behavior change, weight stabilization/loss) and ultimately increase uptake, implementation success, and long-term results. After initial tool development, user-testing interviews (n = 13) were conducted using a think-aloud protocol that provided insight into users' (i.e., healthcare teams) cognitive processes, attitudes, and challenges when using the tool. Overall, the PREVENT tool was perceived to be useful, well-organized, and visually appealing.

4.
BMJ Open ; 11(9): e048425, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34548353

RESUMO

IMPORTANCE: Hypertension is the largest contributor to the Global Burden of Disease. In Rwanda, as in most low-income and middle-income countries, an increasing prevalence of hypertension and its associated morbidity and mortality is causing major healthcare and economic impact. Understanding healthcare systems context in hypertension care is necessary. OBJECTIVE: To study the hypertension healthcare context as perceived by healthcare providers using the Context Assessment for Community Health (COACH) tool. DESIGN: A cross-sectional cohort responded to the COACH questionnaire and a survey about hypertension training. SETTING: Three tertiary care hospitals in Rwanda. PARTICIPANTS: Healthcare professionals (n=223). PRIMARY OUTCOMES AND MEASURES: The COACH tool consists of 49 items with eight subscales: resources, community engagement, commitment to work, informal payment, leadership, work culture, monitoring services for action (5-point Likert Scale) and sources of knowledge (on a 0-1 scale). Four questions surveyed training on hypertension. RESULTS: Responders (n=223, 75% women; 56% aged 20-35 years) included nurses (n=142, 64%, midwives (n=42, 19%), primary care physicians (n=28, 13%) and physician specialists (n=11, 5%)). The subscales commitment to work, leadership, work culture and informal payment scored between 4.7 and 4.1 and the community engagement, monitoring services for action and organizational resources scored between 3.1 and 3.5. Sources of knowledge had a mean score of 0.6±0.3. While 73% reported having attended a didactic hypertension seminar in the past year, only 28% had received long-term training and 51% had <3-year experience working with hypertension care delivery. The majority (99%) indicated a need for additional training in hypertension care. CONCLUSIONS: There is a need for increased and continuous training in Rwanda. Healthcare responders stated a commitment to work and reported supportive leadership, while acknowledging limited resources and no monitoring systems. The COACH tool provides contextual guidance to develop training strategies prior to the implementation of a sustainable hypertension care programme.


Assuntos
Hipertensão , Médicos de Atenção Primária , Estudos Transversais , Medicina Baseada em Evidências , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/terapia , Masculino , Ruanda/epidemiologia , Inquéritos e Questionários
5.
Science ; 373(6558): 1030-1035, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34385354

RESUMO

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.


Assuntos
Genoma Humano , Mutação em Linhagem Germinativa , Algoritmos , Ilhas de CpG , Dano ao DNA , Desmetilação do DNA , Análise Mutacional de DNA , Replicação do DNA , Variação Genética , Células Germinativas , Humanos , Elementos Nucleotídeos Longos e Dispersos , Mutagênese , Oócitos/fisiologia , Transcrição Genética
6.
J Thorac Cardiovasc Surg ; 162(2): e183-e353, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33972115
8.
Front Genet ; 12: 588452, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679876

RESUMO

Background: Indices of left ventricular (LV) structure and geometry represent useful intermediate phenotypes related to LV hypertrophy (LVH), a predictor of cardiovascular (CV) disease (CVD) outcomes. Methods and Results: We conducted an exome-wide association study of LV mass (LVM) adjusted to height2.7, LV internal diastolic dimension (LVIDD), and relative wall thickness (RWT) among 1,364 participants of African ancestry (AAs) in the Hypertension Genetic Epidemiology Network (HyperGEN). Both single-variant and gene-based sequence kernel association tests were performed to examine whether common and rare coding variants contribute to variation in echocardiographic traits in AAs. We then used a data-driven procedure to prioritize and select genes for functional validation using a human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) model. Three genes [myosin VIIA and Rab interacting protein (MYRIP), trafficking protein particle complex 11 (TRAPPC11), and solute carrier family 27 member 6 (SLC27A6)] were prioritized based on statistical significance, variant functional annotations, gene expression in the hiPSC-CM model, and prior biological evidence and were subsequently knocked down in the hiPSC-CM model. Expression profiling of hypertrophic gene markers in the knockdowns suggested a decrease in hypertrophic expression profiles. MYRIP knockdowns showed a significant decrease in atrial natriuretic factor (NPPA) and brain natriuretic peptide (NPPB) expression. Knockdowns of the heart long chain fatty acid (FA) transporter SLC27A6 resulted in downregulated caveolin 3 (CAV3) expression, which has been linked to hypertrophic phenotypes in animal models. Finally, TRAPPC11 knockdown was linked to deficient calcium handling. Conclusions: The three genes are biologically plausible candidates that provide new insight to hypertrophic pathways.

9.
EBioMedicine ; 63: 103157, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33418499

RESUMO

BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants. METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity. FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10-11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10-9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10-9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10-9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10-9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants. INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.


Assuntos
Genômica , Taxa de Filtração Glomerular , Medicina de Precisão , Sequenciamento Completo do Genoma , Alelos , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Masculino , National Heart, Lung, and Blood Institute (U.S.) , Polimorfismo de Nucleotídeo Único , Medicina de Precisão/métodos , Vigilância em Saúde Pública , Característica Quantitativa Herdável , Estados Unidos/epidemiologia
10.
Eur J Hum Genet ; 29(5): 839-850, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33500576

RESUMO

Recent studies consider lifestyle risk score (LRS), an aggregation of multiple lifestyle exposures, in identifying association of gene-lifestyle interaction with disease traits. However, not all cohorts have data on all lifestyle factors, leading to increased heterogeneity in the environmental exposure in collaborative meta-analyses. We compared and evaluated four approaches (Naïve, Safe, Complete and Moderator Approaches) to handle the missingness in LRS-stratified meta-analyses under various scenarios. Compared to "benchmark" results with all lifestyle factors available for all cohorts, the Complete Approach, which included only cohorts with all lifestyle components, was underpowered due to lower sample size, and the Naïve Approach, which utilized all available data and ignored the missingness, was slightly inflated. The Safe Approach, which used all data in LRS-exposed group and only included cohorts with all lifestyle factors available in the LRS-unexposed group, and the Moderator Approach, which handled missingness via moderator meta-regression, were both slightly conservative and yielded almost identical p values. We also evaluated the performance of the Safe Approach under different scenarios. We observed that the larger the proportion of cohorts without missingness included, the more accurate the results compared to "benchmark" results. In conclusion, we generally recommend the Safe Approach, a straightforward and non-inflated approach, to handle heterogeneity among cohorts in the LRS based genome-wide interaction meta-analyses.

11.
J Nucl Cardiol ; 28(4): 1649-1659, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31705425

RESUMO

BACKGROUND: Barth syndrome (BTHS) is a rare X-linked condition resulting in cardiomyopathy, however; the effects of BTHS on myocardial substrate metabolism and its relationships with cardiac high-energy phosphate metabolism and left ventricular (LV) function are unknown. We sought to characterize myocardial glucose, fatty acid (FA), and leucine metabolism in BTHS and unaffected controls and examine their relationships with cardiac high-energy phosphate metabolism and LV function. METHODS/RESULTS: Young adults with BTHS (n = 14) and unaffected controls (n = 11, Control, total n = 25) underwent bolus injections of 15O-water and 1-11C-glucose, palmitate, and leucine and concurrent positron emission tomography imaging. LV function and cardiac high-energy phosphate metabolism were examined via echocardiography and 31P magnetic resonance spectroscopy, respectively. Myocardial glucose extraction fraction (21 ± 14% vs 10 ± 8%, P = .03) and glucose utilization (828.0 ± 470.0 vs 393.2 ± 361.0 µmol·g-1·min-1, P = .02) were significantly higher in BTHS vs Control. Myocardial FA extraction fraction (31 ± 7% vs 41 ± 6%, P < .002) and uptake (0.25 ± 0.04 vs 0.29 ± 0.03 mL·g-1·min-1, P < .002) were significantly lower in BTHS vs Control. Altered myocardial metabolism was associated with lower cardiac function in BTHS. CONCLUSIONS: Myocardial substrate metabolism is altered and may contribute to LV dysfunction in BTHS. Clinical Trials #: NCT01625663.

12.
Mol Psychiatry ; 26(6): 2111-2125, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32372009

RESUMO

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.


Assuntos
Estudo de Associação Genômica Ampla , Hipertensão , Pressão Sanguínea/genética , Epistasia Genética , Loci Gênicos , Humanos , Hipertensão/genética , Polimorfismo de Nucleotídeo Único
13.
Res Sq ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33200126

RESUMO

RATIONALE: The spread of severe acute respiratory syndrome coronavirus-2 has suspended many non-COVID-19 related research activities. Where restarting research activities is permitted, investigators need to evaluate the risks and benefits of resuming data collection and adapt procedures to minimize risk. OBJECTIVES: In the context of the multicountry Household Air Pollution Intervention (HAPIN) trial, we developed a framework to assess the risk of each trial activity and to guide protective measures. Our goal is to maximize integrity of reseach aims while minimizing infection risk based on the latest understanding of the virus. METHODS: We drew on a combination of expert consultations, risk assessment frameworks, institutional guidance and literature to develop our framework. We then systematically graded clinical, behavioral, laboratory and field environmental health research activities in four countries for both adult and child subjects using this framework. RESULTS: Our framework assesses risk based on staff proximity to the participant, exposure time between staff and participants, and potential aerosolization while performing the activity. One of of four risk levels, from minimal to unacceptable, is assigned and guidance on protective measures is provided. Those activities which can potentially aerosolize the virus are deemed the highest risk. CONCLUSIONS: By applying a systematic, procedure-specific approach to risk assessment for each trial activity, we can compare trial activities using the same criteria. This approach allows us to protect our participants and research team and to uphold our ability to deliver on the research commitments we have made to our participants, local communities, and funders. The trial is registered with clinicaltrials.gov (NCT02944682).

14.
Genet Epidemiol ; 44(6): 629-641, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32227373

RESUMO

Although multiple lifestyle exposures simultaneously impact blood pressure (BP) and cardiovascular health, most analysis so far has considered each single lifestyle exposure (e.g., smoking) at a time. Here, we exploit gene-multiple lifestyle exposure interactions to find novel BP loci. For each of 6,254 Framingham Heart Study participants, we computed lifestyle risk score (LRS) value by aggregating the risk of four lifestyle exposures (smoking, alcohol, education, and physical activity) on BP. Using the LRS, we performed genome-wide gene-environment interaction analysis in systolic and diastolic BP using the joint 2 degree of freedom (DF) and 1 DF interaction tests. We identified one genome-wide significant (p < 5 × 10-8 ) and 11 suggestive (p < 1 × 10-6 ) loci. Gene-environment analysis using single lifestyle exposures identified only one of the 12 loci. Nine of the 12 BP loci detected were novel. Loci detected by the LRS were located within or nearby genes with biologically plausible roles in the pathophysiology of hypertension, including KALRN, VIPR2, SNX1, and DAPK2. Our results suggest that simultaneous consideration of multiple lifestyle exposures in gene-environment interaction analysis can identify additional loci missed by single lifestyle approaches.


Assuntos
Pressão Sanguínea/genética , Loci Gênicos , Estilo de Vida , Adulto , Alcoolismo/genética , Escolaridade , Exercício Físico , Feminino , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fumar/genética
15.
Nat Commun ; 10(1): 5121, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719535

RESUMO

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.


Assuntos
Loci Gênicos , Lipídeos/genética , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Sono/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Circ Genom Precis Med ; 12(10): 458-485, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31510778

RESUMO

One of 5 people will develop heart failure over his or her lifetime. Early diagnosis and better understanding of the pathophysiology of this disease are critical to optimal treatment. The "omics"-genomics, pharmacogenomics, epigenomics, proteomics, metabolomics, and microbiomics- of heart failure represent rapidly expanding fields of science that have, to date, not been integrated into a single body of work. The goals of this statement are to provide a comprehensive overview of the current state of these omics as they relate to the development and progression of heart failure and to consider the current and potential future applications of these data for precision medicine with respect to prevention, diagnosis, and therapy.


Assuntos
Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Medicina de Precisão/tendências , American Heart Association , Epigenômica , Insuficiência Cardíaca/microbiologia , Insuficiência Cardíaca/terapia , Humanos , Metabolômica , Microbiota , Proteômica , Estados Unidos
17.
Diabetol Metab Syndr ; 11: 61, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31384309

RESUMO

Background: Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome. Methods: Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment. Results: For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups. Conclusions: These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting.Trial registration ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007.

18.
Glob Heart ; 14(2): 135-141, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31324367

RESUMO

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide and in low- and middle-income countries, and hypertension (HTN) is a major risk factor for CVD. Although effective evidence-based interventions for control of HTN in high-income countries exist, implementation of these in low- and middle-income countries has been challenging due to limited capacity and infrastructure for late-phase translational research. In Rwanda, the 2015 STEPS NCD (STEPwise Approach to Surveillance of Noncommunicable Diseases) risk survey reported an overall prevalence of HTN of 15% (95% confidence interval [CI]: 13.8 to 16.3) for those ages 15 to 64 years; prevalence increased with increasing age to 39% (95% CI: 35.7 to 43.1) for those ages 55 to 64 years; CVD was the third most common cause of mortality (7%). Suboptimal infrastructure and capacity in Rwanda hinders research and community knowledge for HTN control. OBJECTIVES: To address the issue of suboptimal capacity to implement evidence-based interventions in HTN, this project was designed with the following objectives: 1) to develop a regional needs assessment of infrastructure for dissemination and implementation (D & I) strategies for HTN-CVD control; 2) to develop HTN-CVD research capacity through creation of countrywide resources such as core research facilities and training in the fields of HTN-CVD, D & I, and biostatistics; and 3) to engage and train multiple stakeholders in D & I and HTN-CVD evidence-based interventions. METHODS: A weeklong training program in HTN-CVD, biostatistics, and D & I was conducted in Rwanda in August 2018, and pre- and post-D & I training competency questionnaires were administered. RESULTS: Questionnaire results show a statistically significant increase in D & I knowledge and skills as a result of training (full scale pre- to post-test scores: 2.12 ± 0.78 vs. 3.94 ± 0.42; p < 0.0001). CONCLUSIONS: Using principles of community engagement and train-the-trainer methods, we will continue to adapt guidelines and treatments for HTN-CVD developed in high-income countries to the context of Rwanda with the goal of establishing a sustainable platform to address the burden of disease from HTN-CVD.


Assuntos
Pesquisa Biomédica/educação , Cardiologia/educação , Competência Clínica , Educação de Pós-Graduação em Medicina/métodos , Hipertensão/prevenção & controle , Ciência da Implementação , Médicos/normas , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Prevalência , Avaliação de Programas e Projetos de Saúde , Fatores de Risco , Ruanda/epidemiologia
19.
Hum Mol Genet ; 28(15): 2615-2633, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31127295

RESUMO

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.


Assuntos
Pressão Arterial/genética , Interação Gene-Ambiente , Hipertensão/genética , Polimorfismo Genético , Fumar/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiporters/genética , Pressão Sanguínea/genética , Caspase 9/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/etiologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Receptores de Vasopressinas/genética , Transportadores de Sulfato/genética , Proteínas Supressoras de Tumor/genética , Adulto Jovem
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